Abstract
According to Descartes, minds and bodies are distinct kinds of “substance”, and they cannot have causal interactions. However, in neuroscience, the two-way interaction between the brain and peripheral organs is an emerging field of research. Several lines of evidence highlight the importance of such interactions. For example, the peripheral metabolic systems are overwhelmingly regulated by the mind (brain), and anxiety and depression greatly affect the functioning of these systems. Also, psychological stress can cause a variety of physical symptoms, such as bone loss. Moreover, the gut microbiota appears to play a key role in neuropsychiatric and neurodegenerative diseases. Mechanistically, as the command center of the body, the brain can regulate our internal organs and glands through the autonomic nervous system and neuroendocrine system, although it is generally considered to be outside the realm of voluntary control. The autonomic nervous system itself can be further subdivided into the sympathetic and parasympathetic systems. The sympathetic division functions a bit like the accelerator pedal on a car, and the parasympathetic division functions as the brake. The high center of the autonomic nervous system and the neuroendocrine system is the hypothalamus, which contains several subnuclei that control several basic physiological functions, such as the digestion of food and regulation of body temperature. Also, numerous peripheral signals contribute to the regulation of brain functions. Gastrointestinal (GI) hormones, insulin, and leptin are transported into the brain, where they regulate innate behaviors such as feeding, and they are also involved in emotional and cognitive functions. The brain can recognize peripheral inflammatory cytokines and induce a transient syndrome called sick behavior (SB), characterized by fatigue, reduced physical and social activity, and cognitive impairment. In summary, knowledge of the biological basis of the interactions between the central nervous system and peripheral organs will promote the full understanding of how our body works and the rational treatment of disorders. Thus, we summarize current development in our understanding of five types of central-peripheral interactions, including neural control of adipose tissues, energy expenditure, bone metabolism, feeding involving the brain-gut axis and gut microbiota. These interactions are essential for maintaining vital bodily functions, which result in homeostasis, i.e., a natural balance in the body’s systems.
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Abbott, S.B.G., and Saper, C.B. (2017). Median preoptic glutamatergic neurons promote thermoregulatory heat loss and water consumption in mice. J Physiol 595, 6569–6583.
Abdel-Haq, R., Schlachetzki, J.C.M., Glass, C.K., and Mazmanian, S.K. (2019). Microbiome-microglia connections via the gut-brain axis. J Exp Med 216, 41–59.
Abreu-Vieira, G., Xiao, C., Gavrilova, O., and Reitman, M.L. (2015). Integration of body temperature into the analysis of energy expenditure in the mouse. Mol Metab 4, 461–470.
Aho, V.T.E., Pereira, P.A.B., Voutilainen, S., Paulin, L., Pekkonen, E., Auvinen, P., and Scheperjans, F. (2019). Gut microbiota in Parkinson’s disease: temporal stability and relations to disease progression. Ebiomedicine 44, 691–707.
Akkasheh, G., Kashani-Poor, Z., Tajabadi-Ebrahimi, M., Jafari, P., Akbari, H., Taghizadeh, M., Memarzadeh, M.R., Asemi, Z., and Esmaillzadeh, A. (2016). Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition 32, 315–320.
Allison, S.J., Baldock, P., Sainsbury, A., Enriquez, R., Lee, N.J., Lin, E.J. D., Klugmann, M., Klugman, M., During, M., Eisman, J.A., et al. (2006). Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice. J Biol Chem 281, 23436–23444.
Almeida, M., Laurent, M.R., Dubois, V., Claessens, F., O’Brien, C.A., Bouillon, R., Vanderschueren, D., and Manolagas, S.C. (2016). Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97, 135–187.
Amir, S., Shizgal, P., and Rompré, P.P. (1989). Glutamate injection into the suprachiasmatic nucleus stimulates brown fat thermogenesis in the rat. Brain Res 498, 140–144.
Andrew, D., Krout, K.E., and Craig, A.D.B. (2003). Differentiation of lamina I spinomedullary and spinothalamic neurons in the cat. J Comp Neurol 458, 257–271.
Apfelbaum, M., Bostsarron, J., and Lacatis, D. (1971). Effect of caloric restriction and excessive caloric intake on energy expenditure. Am J Clin Nutr 24, 1405–1409.
Bai, L., Mesgarzadeh, S., Ramesh, K.S., Huey, E.L., Liu, Y., Gray, L.A., Aitken, T.J., Chen, Y., Beutler, L.R., Ahn, J.S., et al. (2019). Genetic identification of vagal sensory neurons that control feeding. Cell 179, 1129–1143.e23.
Bajayo, A., Bar, A., Denes, A., Bachar, M., Kram, V., Attar-Namdar, M., Zallone, A., Kovács, K.J., Yirmiya, R., and Bab, I. (2012). Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc Natl Acad Sci USA 109, 15455–15460.
Baldock, P.A., Lee, N.J., Driessler, F., Lin, S., Allison, S., Stehrer, B., Lin, E.J.D., Zhang, L., Enriquez, R.F., Wong, I.P.L., et al. (2009). Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS ONE 4, e8415.
Baldock, P.A., Sainsbury, A., Couzens, M., Enriquez, R.F., Thomas, G.P., Gardiner, E.M., and Herzog, H. (2002). Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 109, 915–921.
Balthasar, N., Dalgaard, L.T., Lee, C.E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R.A., Kenny, C.D., et al. (2005). Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505.
Bamshad, M., Aoki, V.T., Adkison, M.G., Warren, W.S., and Bartness, T.J. (1998). Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am J Physiol 275, R291–R299.
Bamshad, M., Song, C.K., and Bartness, T.J. (1999). CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol 276, R1569–R1578.
Barbara, G., Wang, B., Stanghellini, V., de Giorgio, R., Cremon, C., Di Nardo, G., Trevisani, M., Campi, B., Geppetti, P., Tonini, M., et al. (2007). Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 132, 26–37.
Baribeau, D.A., and Anagnostou, E. (2015). Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. Front Neurosci 9, 335.
Barrett, E., Ross, R.P., O’Toole, P.W., Fitzgerald, G.F., and Stanton, C. (2012). γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 113, 411–417.
Bartelt, A., and Heeren, J. (2014). Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10, 24–36.
Bartness, T.J., and Ryu, V. (2015). Neural control of white, beige and brown adipocytes. Int J Obes Supp 5, S35–S39.
Bartness, T.J., Shrestha, Y.B., Vaughan, C.H., Schwartz, G.J., and Song, C. K. (2010). Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol Cell Endocrinol 318, 34–43.
Bartness, T.J., Song, C.K., and Demas, G.E. (2001). SCN efferents to peripheral tissues: implications for biological rhythms. J Biol Rhythms 16, 196–204.
Beranger, G.E., Pisani, D.F., Castel, J., Djedaini, M., Battaglia, S., Amiaud, J., Boukhechba, F., Ailhaud, G., Michiels, J.F., Heymann, D., et al. (2014). Oxytocin reverses ovariectomy-induced osteopenia and body fat gain. Endocrinology 155, 1340–1352.
Bercik, P., Verdu, E.F., Foster, J.A., Macri, J., Potter, M., Huang, X., Malinowski, P., Jackson, W., Blennerhassett, P., Neufeld, K.A., et al. (2010). Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, 2102–2112.e1.
Berg, A.H., Combs, T.P., Du, X., Brownlee, M., and Scherer, P.E. (2001). The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7, 947–953.
Berthoud, H.R., Carlson, N.R., and Powley, T.L. (1991). Topography of efferent vagal innervation of the rat gastrointestinal tract. Am J Physiol 260, R200–R207.
Betley, J.N., Cao, Z.F.H., Ritola, K.D., and Sternson, S.M. (2013). Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350.
Betley, J.N., Xu, S., Cao, Z.F.H., Gong, R., Magnus, C.J., Yu, Y., and Sternson, S.M. (2015). Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185.
Blaszkiewicz, M., and Townsend, K.L. (2016). Adipose tissue and energy expenditure: central and peripheral neural activation pathways. Curr Obes Rep 5, 241–250.
Blaszkiewicz, M., Willows, J.W., Dubois, A.L., Waible, S., DiBello, K., Lyons, L.L., Johnson, C.P., Paradie, E., Banks, N., Motyl, K., et al. (2019). Neuropathy and neural plasticity in the subcutaneous white adipose depot. PLoS ONE 14, e0221766.
Boonen, S., Kay, R., Cooper, C., Haentjens, P., Vanderschueren, D., Callewaert, F., Milisen, K., and Ferrari, S. (2009). Osteoporosis management: a perspective based on bisphosphonate data from randomised clinical trials and observational databases. Int J Clin Pract 63, 1792–1804.
Bornstein, J.C., and Furness, J.B. (1988). Correlated electrophysiological and histochemical studies of submucous neurons and their contribution to understanding enteric neural circuits. J Auton Nerv Syst 25, 1–13.
Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Tóth, M., Korecka, A., Bakocevic, N., Ng, L.G., Guan, N.L., et al. (2014). The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6, 263ra158.
Bravo, J.A., Forsythe, P., Chew, M.V., Escaravage, E., Savignac, H.M., Dinan, T.G., Bienenstock, J., and Cryan, J.F. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 108, 16050–16055.
Bravo, J.A., Julio-Pieper, M., Forsythe, P., Kunze, W., Dinan, T.G., Bienenstock, J., and Cryan, J.F. (2012). Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol 12, 667–672.
Brierley, S.M. (2010). Molecular basis of mechanosensitivity. Auton Neurosci 153, 58–68.
Brookes, S.J.H., Spencer, N.J., Costa, M., and Zagorodnyuk, V.P. (2013). Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol 10, 286–296.
Buffington, S.A., Di Prisco, G.V., Auchtung, T.A., Ajami, N.J., Petrosino, J.F., and Costa-Mattioli, M. (2016). Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775.
Burokas, A., Moloney, R.D., Dinan, T.G., and Cryan, J.F. (2015). Microbiota regulation of the mammalian gut-brain axis. In: Advances in Applied Microbiology. New York: Academic Press. 1–62.
Cannon, B., and Nedergaard, J. (2004). Brown adipose tissue: function and physiological significance. Physiol Rev 84, 277–359.
Cannon, B., and Nedergaard, J. (2011). Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214, 242–253.
Cao, L., Choi, E.Y., Liu, X., Martin, A., Wang, C., Xu, X., and During, M.J. (2011). White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab 14, 324–338.
Cao, W.H., Fan, W., and Morrison, S.F. (2004). Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience 126, 229–240.
Cao, Y., Wang, H., Wang, Q., Han, X., and Zeng, W. (2018a). Three-dimensional volume fluorescence-imaging of vascular plasticity in adipose tissues. Mol Metab 14, 71–81.
Cao, Y., Wang, H., and Zeng, W. (2018b). Whole-tissue 3D imaging reveals intra-adipose sympathetic plasticity regulated by NGF-TrkA signal in cold-induced beiging. Protein Cell 9, 527–539.
Carabotti, M., Scirocco, A., Maselli, M.A., and Severi, C. (2015). The gutbrain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28, 203–209.
Carlisle, H.J. (1969). Effect of preoptic and anterior hypothalamic lesions on behavioral thermoregulation in the cold. J Comp Physiol Psychol 69, 391–402.
Caron, A., Dungan Lemko, H.M., Castorena, C.M., Fujikawa, T., Lee, S., Lord, C.C., Ahmed, N., Lee, C.E., Holland, W.L., Liu, C., et al. (2018a). POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels. elife 7, e33710.
Caron, A., Lee, S., Elmquist, J.K., and Gautron, L. (2018b). Leptin and brain-adipose crosstalks. Nat Rev Neurosci 19, 153–165.
Cekanaviciute, E., Yoo, B.B., Runia, T.F., Debelius, J.W., Singh, S., Nelson, C.A., Kanner, R., Bencosme, Y., Lee, Y.K., Hauser, S.L., et al. (2017). Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci USA 114, 10713–10718.
Celi, F.S., Brychta, R.J., Linderman, J.D., Butler, P.W., Alberobello, A.T., Smith, S., Courville, A.B., Lai, E.W., Costello, R., Skarulis, M.C., et al. (2010). Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults. Eur J Endocrinol 163, 863–872.
Chang, H.Y., Mashimo, H., and Goyal, R.K. (2003). Musings on the wanderer: What’s new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut. Am J Physiol Gastrointest Liver Physiol 284, G357–G366.
Chao, P.T., Yang, L., Aja, S., Moran, T.H., and Bi, S. (2011). Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab 13, 573–583.
Chen, C., Ahn, E.H., Kang, S.S., Liu, X., Alam, A., and Ye, K. (2020a). Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model. Sci Adv 6, eaba0466.
Chen, J., Cheng, M., Wang, L., Zhang, L., Xu, D., Cao, P., Wang, F., Herzog, H., Song, S., and Zhan, C. (2020b). A Vagal-NTS neural pathway that stimulates feeding. Curr Biol 30, 3986–3998.e5.
Chen, Y., Lin, Y.C., Kuo, T.W., and Knight, Z.A. (2015). Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841.
Chi, J., Wu, Z., Choi, C.H.J., Nguyen, L., Tegegne, S., Ackerman, S.E., Crane, A., Marchildon, F., Tessier-Lavigne, M., and Cohen, P. (2018). Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab 27, 226–236.e3.
Cinti, S. (2005). The adipose organ. Prostaglandins Leukot Essent Fatty Acids 73, 9–15.
Cinti, S. (2018a). Adipose organ development and remodeling. Compr Physiol 8, 1357–1431.
Cinti, S. (2018b). Pink adipocytes. Trends Endocrinol Metab 29, 651–666.
Cintron-Colon, R., Johnson, C.W., Montenegro-Burke, J.R., Guijas, C., Faulhaber, L., Sanchez-Alavez, M., Aguirre, C.A., Shankar, K., Singh, M., Galmozzi, A., et al. (2019). Activation of kappa opioid receptor regulates the hypothermic response to calorie restriction and limits body weight loss. Curr Biol 29, 4291–4299.e4.
Cohen, P., and Spiegelman, B.M. (2015). Brown and beige fat: molecular parts of a thermogenic machine. Diabetes 64, 2346–2351.
Colaianni, G., Sun, L., Zaidi, M., and Zallone, A. (2015). The “love hormone” oxytocin regulates the loss and gain of the fat-bone relationship. Front Endocrinol 6.
Colica, C., Avolio, E., Bollero, P., Costa de Miranda, R., Ferraro, S., Sinibaldi Salimei, P., De Lorenzo, A., and Di Renzo, L. (2017). Evidences of a new psychobiotic formulation on body composition and anxiety. Mediators Inflamm 2017, 1–10.
Collins, S., Kuhn, C.M., Petro, A.E., Swick, A.G., Chrunyk, B.A., and Surwit, R.S. (1996). Role of leptin in fat regulation. Nature 380, 677.
Conceição, E.P.S., Madden, C.J., and Morrison, S.F. (2018). Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis. Acta Physiol 225, e13213.
Conti, B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M.C., Lucero, J., Brownell, S., Fabre, V., Huitron-Resendiz, S., Henriksen, S., Zorrilla, E.P., et al. (2006). Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825–828.
Costa, M., Brookes, S.H.J., and Zagorodnyuk, V. (2004). How many kinds of visceral afferents? Gut 53, 1ii–4.
Cousin, B., Cinti, S., Morroni, M., Raimbault, S., Ricquier, D., Pénicaud, L., and Casteilla, L. (1992). Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 103, 931–942.
Cypess, A.M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F.C., Palmer, E.L., Tseng, Y.H., Doria, A., et al. (2009). Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360, 1509–1517.
Cypess, A.M., White, A.P., Vernochet, C., Schulz, T.J., Xue, R., Sass, C.A., Huang, T.L., Roberts-Toler, C., Weiner, L.S., Sze, C., et al. (2013). Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19, 635–639.
Dénes, A., Boldogkoi, Z., Uhereczky, G., Hornyák, A., Rusvai, M., Palkovits, M., and Kovács, K.J. (2005). Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience 134, 947–963.
Dalile, B., Van Oudenhove, L., Vervliet, B., and Verbeke, K. (2019). The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 16, 461–478.
Dan, Z., Mao, X., Liu, Q., Guo, M., Zhuang, Y., Liu, Z., Chen, K., Chen, J., Xu, R., Tang, J., et al. (2020). Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder. Gut Microbes 11, 1246–1267.
de Jong, J.M.A., Sun, W., Pires, N.D., Frontini, A., Balaz, M., Jespersen, N. Z., Feizi, A., Petrovic, K., Fischer, A.W., Bokhari, M.H., et al. (2019). Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat Metab 1, 830–843.
de Lartigue, G. (2016). Role of the vagus nerve in the development and treatment of diet-induced obesity. J Physiol 594, 5791–5815.
De Matteis, R., Ricquier, D., and Cinti, S. (1998). TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study. J Neurocytology 27, 877–886.
Desautels, M., Dulos, R.A., and Mozaffari, B. (1986). Selective loss of uncoupling protein from mitochondria of surgically denervated brown adipose tissue of cold-acclimated mice. Biochem Cell Biol 64, 1125–1134.
Deschasaux, M., Bouter, K.E., Prodan, A., Levin, E., Groen, A.K., Herrema, H., Tremaroli, V., Bakker, G.J., Attaye, I., Pinto-Sietsma, S.J., et al. (2018). Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat Med 24, 1526–1531.
Diculescu, I., and Stoica, M. (1970). Fluorescence histochemical investigation on the adrenergic innervation of the white adipose tissue in the rat. J Neuro-Viscer Relat 32, 25–36.
Dinan, T.G., Stanton, C., and Cryan, J.F. (2013). Psychobiotics: a novel class of psychotropic. Biol Psychiatry 74, 720–726.
Ding, W., Zhang, C., Wang, B., Zhou, X., Sun, L., Zhong, S., Liu, J., Zhang, J., Wang, X., and Wu, Q. (2021). Loss of the centrosomal protein Cenpj leads to dysfunction of the hypothalamus and obesity in mice. Sci China Life Sci 64, 419–433.
Dodd, G.T., Decherf, S., Loh, K., Simonds, S.E., Wiede, F., Balland, E., Merry, T.L., Münzberg, H., Zhang, Z.Y., Kahn, B.B., et al. (2015). Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104.
Dodd, G.T., Worth, A.A., Nunn, N., Korpal, A.K., Bechtold, D.A., Allison, M.B., MyersJr., M.G., Statnick, M.A., and Luckman, S.M. (2014). The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab 20, 639–649.
Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A.F., Beil, F.T., Shen, J., Vinson, C., Rueger, J.M., and Karsenty, G. (2000). Leptin inhibits bone formation through a hypothalamic relay. Cell 100, 197–207.
Dulloo, A.G., and Miller, D.S. (1984). Energy balance following sympathetic denervation of brown adipose tissue. Can J Physiol Pharmacol 62, 235–240.
Egerod, K.L., Petersen, N., Timshel, P.N., Rekling, J.C., Wang, Y., Liu, Q., Schwartz, T.W., and Gautron, L. (2018). Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms. Mol Metab 12, 62–75.
Eimar, H., Tamimi, I., Murshed, M., and Tamimi, F. (2013). Cholinergic regulation of bone. J Musculoskelet Neuronal Interact 13, 124–132.
Ek, M., Kurosawa, M., Lundeberg, T., and Ericsson, A. (1998). Activation of vagal afferents after intravenous injection of interleukin-1β: role of endogenous prostaglandins. J Neurosci 18, 9471–9479.
Elefteriou, F., Ahn, J.D., Takeda, S., Starbuck, M., Yang, X., Liu, X., Kondo, H., Richards, W.G., Bannon, T.W., Noda, M., et al. (2005). Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520.
Erny, D., Hrabě de Angelis, A.L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18, 965–977.
Espinosa-Medina, I., Saha, O., Boismoreau, F., Chettouh, Z., Rossi, F., Richardson, W.D., and Brunet, J.F. (2016). The sacral autonomic outflow is sympathetic. Science 354, 893–897.
Fan, W., Ellacott, K.L.J., Halatchev, I.G., Takahashi, K., Yu, P., and Cone, R.D. (2004). Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci 7, 335–336.
Farman, H.H., Windahl, S.H., Westberg, L., Isaksson, H., Egecioglu, E., Schele, E., Ryberg, H., Jansson, J.O., Tuukkanen, J., Koskela, A., et al. (2016). Female mice lacking estrogen receptor-α in hypothalamic proopiomelanocortin (POMC) neurons display enhanced estrogenic response on cortical bone mass. Endocrinology 157, 3242–3252.
Fishman, R.B., and Dark, J. (1987). Sensory innervation of white adipose tissue. Am J Physiol 253, R942–R944.
Flower, D.R. (1996). The lipocalin protein family: structure and function. Biochem J 318, 1–14.
Frame, L.A., Costa, E., and Jackson, S.A. (2020). Current explorations of nutrition and the gut microbiome: a comprehensive evaluation of the review literature. Nutr Rev 78, 798–812.
François, M., Torres, H., Huesing, C., Zhang, R., Saurage, C., Lee, N., Qualls-Creekmore, E., Yu, S., Morrison, C.D., Burk, D., et al. (2019). Sympathetic innervation of the interscapular brown adipose tissue in mouse. Ann NY Acad Sci 1454, 3–13.
Fülling, C., Dinan, T.G., and Cryan, J.F. (2019). Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998–1002.
Furness, J.B., Jones, C., Nurgali, K., and Clerc, N. (2004). Intrinsic primary afferent neurons and nerve circuits within the intestine. Prog Neurobiol 72, 143–164.
Garfield, A.S., Li, C., Madara, J.C., Shah, B.P., Webber, E., Steger, J.S., Campbell, J.N., Gavrilova, O., Lee, C.E., Olson, D.P., et al. (2015). A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18, 863–871.
Garg, A. (2011). Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 96, 3313–3325.
Garretson, J.T., Szymanski, L.A., Schwartz, G.J., Xue, B., Ryu, V., and Bartness, T.J. (2016). Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol Metab 5, 626–634.
Garrett, W.S. (2019). The gut microbiota and colon cancer. Science 364, 1133–1135.
Geerling, J.C., Kim, M., Mahoney, C.E., Abbott, S.B.G., Agostinelli, L.J., Garfield, A.S., Krashes, M.J., Lowell, B.B., and Scammell, T.E. (2016). Genetic identity of thermosensory relay neurons in the lateral parabrachial nucleus. Am J Physiol Regul Integr Comp Physiol 310, R41–R54.
Gibson, G.R., Hutkins, R., Sanders, M.E., Prescott, S.L., Reimer, R.A., Salminen, S.J., Scott, K., Stanton, C., Swanson, K.S., Cani, P.D., et al. (2017). Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 14, 491–502.
Gillis, R.A., Dias Souza, J., Hicks, K.A., Mangel, A.W., Pagani, F.D., Hamilton, B.L., Garvey3rd, T.Q., Pace, D.G., Browne, R.K., and Norman, W.P. (1987). Inhibitory control of proximal colonic motility by the sympathetic nervous system. Am J Physiol 253, G531–G539.
Giordano, A., Morroni, M., Carle, F., Gesuita, R., Marchesi, G.F., and Cinti, S. (1998). Sensory nerves affect the recruitment and differentiation of rat periovarian brown adipocytes during cold acclimation. J Cell Sci 111, 2587–2594.
Giordano, A., Morroni, M., Santone, G., Marchesi, G.F., and Cinti, S. (1996). Tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide and vasoactive intestinal peptide in nerves of rat periovarian adipose tissue: an immunohistochemical and ultrastructural investigation. J Neurocytol 25, 125–136.
Gorecki, A.M., Preskey, L., Bakeberg, M.C., Kenna, J.E., Gildenhuys, C., MacDougall, G., Dunlop, S.A., Mastaglia, F.L., Akkari, P.A., Koengten, F., et al. (2019). Altered gut microbiome in Parkinson’s Disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model. Front Neurosci 13, 839.
Greenwood, B., Tremblay, L., and Davison, J.S. (1987). Sympathetic control of motility, fluid transport, and transmural potential difference in the rabbit ileum. Am J Physiol 253, G726–G729.
Gropp, E., Shanabrough, M., Borok, E., Xu, A.W., Janoschek, R., Buch, T., Plum, L., Balthasar, N., Hampel, B., Waisman, A., et al. (2005). Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8, 1289–1291.
Guilherme, A., Henriques, F., Bedard, A.H., and Czech, M.P. (2019). Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat Rev Endocrinol 15, 207–225.
Guilherme, A., Pedersen, D.J., Henchey, E., Henriques, F.S., Danai, L.V., Shen, Y., Yenilmez, B., Jung, D.Y., Kim, J.K., Lodhi, I.J., et al. (2017). Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming. Mol Metab 6, 781–796.
Guilherme, A., Pedersen, D.J., Henriques, F., Bedard, A.H., Henchey, E., Kelly, M., Morgan, D.A., Rahmouni, K., and Czech, M.P. (2018). Neuronal modulation of brown adipose activity through perturbation of white adipocyte lipogenesis. Mol Metab 16, 116–125.
Guo, L., Winzer, T., Yang, X., Li, Y., Ning, Z., He, Z., Teodor, R., Lu, Y., Bowser, T.A., Graham, I.A., et al. (2018). The opium poppy genome and morphinan production. Science 362, 343–347.
Hampton, T. (2016). Ongoing research points to key role of gut microbes in cardiovascular health. Circulation 134, 1687–1688.
Han, W., Tellez, L.A., Perkins, M.H., Perez, I.O., Qu, T., Ferreira, J., Ferreira, T.L., Quinn, D., Liu, Z.W., Gao, X.B., et al. (2018a). A neural circuit for gut-induced reward. Cell 175, 887–888.
Han, Y., You, X., Xing, W., Zhang, Z., and Zou, W. (2018b). Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res 6, 16.
Harding, E.C., Yu, X., Miao, A., Andrews, N., Ma, Y., Ye, Z., Lignos, L., Miracca, G., Ba, W., Yustos, R., et al. (2018). A neuronal Hub binding sleep initiation and body cooling in response to a warm external stimulus. Curr Biol 28, 2263–2273.e4.
Haynes, W.G., Morgan, D.A., Walsh, S.A., Mark, A.L., and Sivitz, W.I. (1997). Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100, 270–278.
Henriques, F., Bedard, A.H., Guilherme, A., Kelly, M., Chi, J., Zhang, P., Lifshitz, L.M., Bellvé, K., Rowland, L.A., Yenilmez, B., et al. (2020). Single-cell RNA profiling reveals adipocyte to macrophage signaling sufficient to enhance thermogenesis. Cell Rep 32, 107998.
Holland, W.L., Miller, R.A., Wang, Z.V., Sun, K., Barth, B.M., Bui, H.H., Davis, K.E., Bikman, B.T., Halberg, N., Rutkowski, J.M., et al. (2011). Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17, 55–63.
Holsboer, F. (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501.
Hooper, L.V., Littman, D.R., and Macpherson, A.J. (2012). Interactions between the microbiota and the immune system. Science 336, 1268–1273.
Hori, M., Shimizu, Y., and Fukumoto, S. (2011). Minireview: fibroblast growth factor 23 in phosphate homeostasis and bone metabolism. Endocrinology 152, 4–10.
Hrvatin, S., Sun, S., Wilcox, O.F., Yao, H., Lavin-Peter, A.J., Cicconet, M., Assad, E.G., Palmer, M.E., Aronson, S., Banks, A.S., et al. (2020). Neurons that regulate mouse torpor. Nature 583, 115–121.
Huang, S., Li, Z., Liu, Y., Gao, D., Zhang, X., Hao, J., and Yang, F. (2019). Neural regulation of bone remodeling: Identifying novel neural molecules and pathways between brain and bone. J Cell Physiol 234, 5466–5477.
Hugenholtz, F., and de Vos, W.M. (2018). Mouse models for human intestinal microbiota research: a critical evaluation. Cell Mol Life Sci 75, 149–160.
Idelevich, A., Sato, K., Nagano, K., Rowe, G., Gori, F., and Baron, R. (2018). Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent. J Clin Invest 128, 2626–2641.
Ishibashi, J., and Seale, P. (2010). Beige can be slimming. Science 328, 1113–1114.
Jacobsson, A., Stadler, U., Glotzer, M.A., and Kozak, L.P. (1985). Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression. J Biol Chem 260, 16250–16254.
James, W. (1948). What is emotion? 1884. In: Dennis, W., ed. Readings in the History of Psychology. 290–303.
Jangi, S., Gandhi, R., Cox, L.M., Li, N., von Glehn, F., Yan, R., Patel, B., Mazzola, M.A., Liu, S., Glanz, B.L., et al. (2016). Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 7, 12015.
Jespersen, N.Z., Larsen, T.J., Peijs, L., Daugaard, S., Homøe, P., Loft, A., de Jong, J., Mathur, N., Cannon, B., Nedergaard, J., et al. (2013). A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 17, 798–805.
Jiang, H., Ding, X., Cao, Y., Wang, H., and Zeng, W. (2017). Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell Metab 26, 686–692.e3.
Jiang, L., Su, H., Wu, X., Shen, H., Kim, M.H., Li, Y., MyersJr, M.G., Owyang, C., and Rui, L. (2020). Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease. Nat Commun 11, 1517.
Kaelberer, M.M., Buchanan, K.L., Klein, M.E., Barth, B.B., Montoya, M. M., Shen, X., and Bohórquez, D.V. (2018). A gut-brain neural circuit for nutrient sensory transduction. Science 361.
Kajimura, S., Spiegelman, B.M., and Seale, P. (2015). Brown and beige fat: physiological roles beyond heat generation. Cell Metab 22, 546–559.
Kalra, S.P., and Kalra, P.S. (2004). Hypothalamic regulation of appetite and obesity. In: Martini, L., ed. Encyclopedia of Endocrine Diseases. New York, Elsevier. 699–706.
Kalsbeek, A., Bruinstroop, E., Yi, C.X., Klieverik, L.P., La Fleur, S.E., and Fliers, E. (2010). Hypothalamic control of energy metabolism via the autonomic nervous system. Ann N Y Acad Sci 1212, 114–129.
Kang, D.W., Adams, J.B., Gregory, A.C., Borody, T., Chittick, L., Fasano, A., Khoruts, A., Geis, E., Maldonado, J., McDonough-Means, S., et al. (2017). Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10.
Kang, D.W., Park, J.G., Ilhan, Z.E., Wallstrom, G., Labaer, J., Adams, J.B., and Krajmalnik-Brown, R. (2013). Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE 8, e68322.
Karnatovskaia, L.V., Wartenberg, K.E., and Freeman, W.D. (2014). Therapeutic hypothermia for neuroprotection. Neurohospitalist 4, 153–163.
Karsenty, G., and Oury, F. (2010). The central regulation of bone mass, the first link between bone remodeling and energy metabolism. J Clin Endocrinol Metab 95, 4795–4801.
Kataoka, N., Hioki, H., Kaneko, T., and Nakamura, K. (2014). Psychological stress activates a dorsomedial hypothalamus-medullary raphe circuit driving brown adipose tissue thermogenesis and hyperthermia. Cell Metab 20, 346–358.
Kataoka, N., Shima, Y., Nakajima, K., and Nakamura, K. (2020). A central master driver of psychosocial stress responses in the rat. Science 367, 1105–1112.
Kellermayer, R. (2019). Fecal microbiota transplantation: great potential with many challenges. Transl Gastroenterol Hepatol 4, 40.
Kelly, J.R., Borre, Y., O’Brien, C., Patterson, E., El Aidy, S., Deane, J., Kennedy, P.J., Beers, S., Scott, K., Moloney, G., et al. (2016). Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 82, 109–118.
Khrimian, L., Obri, A., and Karsenty, G. (2017). Modulation of cognition and anxiety-like behavior by bone remodeling. Mol Metab 6, 1610–1615.
Kim, J.G., Sun, B.H., Dietrich, M.O., Koch, M., Yao, G.Q., Diano, S., Insogna, K., and Horvath, T.L. (2015). AgRP neurons regulate bone mass. Cell Rep 13, 8–14.
Kim, K.W., Zhao, L., Donato Jose, J., Kohno, D., Xu, Y., Elias, C.F., Lee, C., Parker, K.L., and Elmquist, J.K. (2011). Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc Natl Acad Sci USA 108, 10673–10678.
Kim, M.S., Kim, Y., Choi, H., Kim, W., Park, S., Lee, D., Kim, D.K., Kim, H.J., Choi, H., Hyun, D.W., et al. (2020a). Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut 69, 283–294.
Kim, S.J., Jeong, Y.T., Jeong, S.R., Park, M., Go, H.S., Kim, M.Y., Seong, J.K., Kim, K.W., Seo, J.T., Kim, C.H., et al. (2020b). Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3. Exp Mol Med 52, 793–803.
Kondo, H., and Togari, A. (2011). Continuous treatment with a low-dose β-agonist reduces bone mass by increasing bone resorption without suppressing bone formation. Calcif Tissue Int 88, 23–32.
Kong, D., Tong, Q., Ye, C., Koda, S., Fuller, P.M., Krashes, M.J., Vong, L., Ray, R.S., Olson, D.P., and Lowell, B.B. (2012). GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151, 645–657.
Kosmidis, S., Polyzos, A., Harvey, L., Youssef, M., Denny, C.A., Dranovsky, A., and Kandel, E.R. (2018). RbAp48 protein is a critical component of GPR158/OCN signaling and ameliorates age-related memory loss. Cell Rep 25, 959–973.e6.
Krashes, M.J., Koda, S., Ye, C.P., Rogan, S.C., Adams, A.C., Cusher, D.S., Maratos-Flier, E., Roth, B.L., and Lowell, B.B. (2011). Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428.
Krashes, M.J., Lowell, B.B., and Garfield, A.S. (2016). Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci 19, 206–219.
Kroeger, D., Absi, G., Gagliardi, C., Bandaru, S.S., Madara, J.C., Ferrari, L.L., Arrigoni, E., Münzberg, H., Scammell, T.E., Saper, C.B., et al. (2018). Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat Commun 9, 4129.
Lai, W.T., Deng, W.F., Xu, S.X., Zhao, J., Xu, D., Liu, Y.H., Guo, Y.Y., Wang, M.B., He, F.S., Ye, S.W., et al. (2021). Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in major depressive disorder patients. Psychol Med 51, 90–101.
Landsberg, L., Young, J.B., Leonard, W.R., Linsenmeier, R.A., and Turek, F.W. (2009). Is obesity associated with lower body temperatures? Core temperature: a forgotten variable in energy balance. Metabolism 58, 871–876.
Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., Almeida, M., Arumugam, M., Batto, J.M., Kennedy, S., et al. (2013). Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546.
Lean, M.E.J., James, W.P.T., Jennings, G., and Trayhurn, P. (1986). Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin Sci 71, 291–297.
Leitner, B.P., Huang, S., Brychta, R.J., Duckworth, C.J., Baskin, A.S., McGehee, S., Tal, I., Dieckmann, W., Gupta, G., Kolodny, G.M., et al. (2017). Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci USA 114, 8649–8654.
Leiva-Gea, I., Sánchez-Alcoholado, L., Martín-Tejedor, B., Castellano-Castillo, D., Moreno-Indias, I., Urda-Cardona, A., Tinahones, F.J., Fernández-García, J.C., and Queipo-Ortuño, M.I. (2018). Gut microbiota differs in composition and functionality between children with type 1 diabetes and MODY2 and healthy control subjects: a case-control study. Diabetes Care 41, 2385–2395.
Li, B., Jiang, Y., Sun, J., Liang, J., and Jin, Y. (2015). MR spectroscopy for assessing the effects of oxytocin on marrow adipogenesis induced by glucocorticoid in rabbits. Acta Radiol 57, 701–707.
Li, X., Liang, S., Xia, Z., Qu, J., Liu, H., Liu, C., Yang, H., Wang, J., Madsen, L., Hou, Y., et al. (2018). Establishment of a Macaca fascicularis gut microbiome gene catalog and comparison with the human, pig, and mouse gut microbiomes. GigaScience 7.
Li, Y., Luo, Z.Y., Hu, Y.Y., Bi, Y.W., Yang, J.M., Zou, W.J., Song, Y.L., Li, S., Shen, T., Li, S.J., et al. (2020). The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice. Microbiome 8, 120.
Li, Z., Hao, J., Duan, X., Wu, N., Zhou, Z., Yang, F., Li, J., Zhao, Z., and Huang, S. (2017). The role of semaphorin 3A in bone remodeling. Front Cell Neurosci 11.
Lidell, M.E., Betz, M.J., Dahlqvist Leinhard, O., Heglind, M., Elander, L., Slawik, M., Mussack, T., Nilsson, D., Romu, T., Nuutila, P., et al. (2013). Evidence for two types of brown adipose tissue in humans. Nat Med 19, 631–634.
Liedtke, W.B. (2017). Deconstructing mammalian thermoregulation. Proc Natl Acad Sci USA 114, 1765–1767.
Lin, T., Wang, C., Cai, X.Z., Zhao, X., Shi, M.M., Ying, Z.M., Yuan, F.Z., Guo, C., and Yan, S.G. (2012). Comparison of clinical efficacy and safety between denosumab and alendronate in postmenopausal women with osteoporosis: a meta-analysis. Int J Clin Pract 66, 399–408.
Liu, H., Kishi, T., Roseberry, A.G., Cai, X., Lee, C.E., Montez, J.M., Friedman, J.M., and Elmquist, J.K. (2003). Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 23, 7143–7154.
Liu, R., Hong, J., Xu, X., Feng, Q., Zhang, D., Gu, Y., Shi, J., Zhao, S., Liu, W., Wang, X., et al. (2017). Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med 23, 859–868.
Liu, R.T., Rowan-Nash, A.D., Sheehan, A.E., Walsh, R.F.L., Sanzari, C.M., Korry, B.J., and Belenky, P. (2020). Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults. Brain Behav Immun 88, 308–324.
Loewy, A.D., and Spyer, K.M. (1990). Central Regulation of Autonomic Functions. Oxford: Oxford University Press.
Logsdon, A.F., Erickson, M.A., Rhea, E.M., Salameh, T.S., and Banks, W. A. (2018). Gut reactions: how the blood-brain barrier connects the microbiome and the brain. Exp Biol Med 243, 159–165.
Loncar, D. (1991). Convertible adipose tissue in mice. Cell Tissue Res 266, 149–161.
Lowell, B.B., S-Susulic, V., Hamann, A., Lawitts, J.A., Himms-Hagen, J., Boyer, B.B., Kozak, L.P., and Flier, J.S. (1993). Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742.
Lundgren, O. (2000). Sympathetic input into the enteric nervous system. Gut 47, 33iv–35.
Luo, F., Mu, Y., Gao, C., Xiao, Y., Zhou, Q., Yang, Y., Ni, X., Shen, W.L., and Yang, J. (2019). Whole-brain patterns of the presynaptic inputs and axonal projections of BDNF neurons in the paraventricular nucleus. J Genet Genomics 46, 31–40.
Luquet, S., Perez, F.A., Hnasko, T.S., and Palmiter, R.D. (2005). NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685.
Lyte, M., Vulchanova, L., and Brown, D.R. (2011). Stress at the intestinal surface: catecholamines and mucosa-bacteria interactions. Cell Tissue Res 343, 23–32.
Machado, N.L.S., Abbott, S.B.G., Resch, J.M., Zhu, L., Arrigoni, E., Lowell, B.B., Fuller, P.M., Fontes, M.A.P., and Saper, C.B. (2018). A glutamatergic hypothalamomedullary circuit mediates thermogenesis, but not heat conservation, during stress-induced hyperthermia. Curr Biol 28, 2291–2301.e5.
Mancuso, C., and Santangelo, R. (2018). Alzheimer’s disease and gut microbiota modifications: the long way between preclinical studies and clinical evidence. Pharmacol Res 129, 329–336.
Mayer, E.A. (2011). Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 12, 453–466.
Mayer, E.A., Savidge, T., and Shulman, R.J. (2014). Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 146, 1500–1512.
McDermott, J.R., Leslie, F.C., D’Amato, M., Thompson, D.G., Grencis, R. K., and McLaughlin, J.T. (2006). Immune control of food intake: enteroendocrine cells are regulated by CD4+ T lymphocytes during small intestinal inflammation. Gut 55, 492–497.
Merritt, K., Egerton, A., Kempton, M.J., Taylor, M.J., and McGuire, P.K. (2016). Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73, 665–674.
Moradi, S., Shab-Bidar, S., Alizadeh, S., and Djafarian, K. (2017). Association between sleep duration and osteoporosis risk in middle-aged and elderly women: a systematic review and meta-analysis of observational studies. Metabolism 69, 199–206.
Morgan, J.M., Hawley, W.L., Chenoweth, A.I., Retan, W.J., and Diethelm, A.G. (1974). Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch Intern Med 134, 549–552.
Morrison, S.F. (2018). Efferent neural pathways for the control of brown adipose tissue thermogenesis and shivering. Handb Clin Neurol 156, 281–303.
Morrison, S.F., Madden, C.J., and Tupone, D. (2014). Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 19, 741–756.
Morrison, S.F., and Nakamura, K. (2011). Central neural pathways for thermoregulation. Front Biosci 16, 74–104.
Morrison, S.F., Ramamurthy, S., and Young, J.B. (2000). Reduced rearing temperature augments responses in sympathetic outflow to brown adipose tissue. J Neurosci 20, 9264–9271.
Mosialou, I., Shikhel, S., Liu, J.M., Maurizi, A., Luo, N., He, Z., Huang, Y., Zong, H., Friedman, R.A., Barasch, J., et al. (2017). MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543, 385–390.
Murano, I., Barbatelli, G., Giordano, A., and Cinti, S. (2009). Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J Anat 214, 171–178.
Nakamura, K., and Morrison, S.F. (2008a). Preoptic mechanism for cold-defensive responses to skin cooling. J Physiol 586, 2611–2620.
Nakamura, K., and Morrison, S.F. (2008b). A thermosensory pathway that controls body temperature. Nat Neurosci 11, 62–71.
Nakamura, Y., Nakamura, K., and Morrison, S.F. (2009). Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions. Neuroscience 161, 614–620.
Narum, S., Westergren, T., and Klemp, M. (2014). Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 4, e004587.
Nayak, S., Edwards, D.L., Saleh, A.A., and Greenspan, S.L. (2015). Systematic review and meta-analysis of the performance of clinical risk assessment instruments for screening for osteoporosis or low bone density. Osteoporos Int 26, 1543–1554.
Nedergaard, J., Bengtsson, T., and Cannon, B. (2007). Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293, E444–E452.
Nguyen, T.T., Kosciolek, T., Daly, R.E., Vázquez-Baeza, Y., Swafford, A., Knight, R., and Jeste, D.V. (2021). Gut microbiome in Schizophrenia: altered functional pathways related to immune modulation and atherosclerotic risk. Brain Behav Immun 91, 245–256.
Nishiwaki, H., Ito, M., Ishida, T., Hamaguchi, T., Maeda, T., Kashihara, K., Tsuboi, Y., Ueyama, J., Shimamura, T., Mori, H., et al. (2020). Meta-analysis of gut dysbiosis in Parkinson’s disease. Mov Disord 35, 1626–1635.
Nnodim, J.O., and Lever, J.D. (1988). Neural and vascular provisions of rat interscapular brown adipose tissue. Am J Anat 182, 283–293.
Nobuhara, Y., Ueki, S., and Takeuchi, K. (1985). Influence of prednisolone on gastric alkaline response in rat stomach. Digest Dis Sci 30, 1166–1173.
Ntranos, A., and Casaccia, P. (2018). The microbiome-gut-behavior axis: crosstalk between the gut microbiome and oligodendrocytes modulates behavioral responses. Neurotherapeutics 15, 31–35.
O’Mahony, S.M., Clarke, G., Borre, Y.E., Dinan, T.G., and Cryan, J.F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277, 32–48.
Obri, A., Khrimian, L., Karsenty, G., and Oury, F. (2018). Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol 14, 174–182.
Ochoa-Repáraz, J., Mielcarz, D.W., Begum-Haque, S., and Kasper, L.H. (2011). Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol 69, 240–247.
Oka, T., Oka, K., and Hori, T. (2001). Mechanisms and mediators of psychological stress-induced rise in core temperature. Psychosom Med 63, 476–486.
Oldfield, B.J., Giles, M.E., Watson, A., Anderson, C., Colvill, L.M., and McKinley, M.J. (2002). The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110, 515–526.
Olm, M.R., Bhattacharya, N., Crits-Christoph, A., Firek, B.A., Baker, R., Song, Y.S., Morowitz, M.J., and Banfield, J.F. (2019). Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella, and fimbriae-encoding bacteria. Sci Adv 5, eaax5727.
Osaka, T. (2004). Cold-induced thermogenesis mediated by GABA in the preoptic area of anesthetized rats. Am J Physiol Regul Integr Comp Physiol 287, R306–R313.
Ouellet, V., Routhier-Labadie, A., Bellemare, W., Lakhal-Chaieb, L., Turcotte, E., Carpentier, A.C., and Richard, D. (2011). Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab 96, 192–199.
Oury, F., Khrimian, L., Denny, C.A., Gardin, A., Chamouni, A., Goeden, N., Huang, Y., Lee, H., Srinivas, P., Gao, X.B., et al. (2013). Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155, 228–241.
Oury, F., Yadav, V.K., Wang, Y., Zhou, B., Liu, X.S., Guo, X.E., Tecott, L. H., Schutz, G., Means, A.R., and Karsenty, G. (2010). CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons. Genes Dev 24, 2330–2342.
Padilla, S.L., Johnson, C.W., Barker, F.D., Patterson, M.A., and Palmiter, R.D. (2018). A neural circuit underlying the generation of hot flushes. Cell Rep 24, 271–277.
Pearson-Leary, J., Zhao, C., Bittinger, K., Eacret, D., Luz, S., Vigderman, A.S., Dayanim, G., and Bhatnagar, S. (2020). The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 25, 1068–1079.
Perez-Burgos, A., Wang, B., Mao, Y.K., Mistry, B., McVey Neufeld, K.A., Bienenstock, J., and Kunze, W. (2013). Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. Am J Physiol Gastrointest Liver Physiol 304, G211–G220.
Perez-Burgos, A., Mao, Y.K., Bienenstock, J., and Kunze, W.A. (2014). The gut-brain axis rewired: adding a functional vagal nicotinic “sensory synapse”. FASEB J 28, 3064–3074.
Petrovic, N., Walden, T.B., Shabalina, I.G., Timmons, J.A., Cannon, B., and Nedergaard, J. (2010). Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 285, 7153–7164.
Piñol, R.A., Zahler, S.H., Li, C., Saha, A., Tan, B.K., Škop, V., Gavrilova, O., Xiao, C., Krashes, M.J., and Reitman, M.L. (2018). Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake. Nat Neurosci 21, 1530–1540.
Pirzgalska, R.M., Seixas, E., Seidman, J.S., Link, V.M., Sánchez, N.M., Mahú, I., Mendes, R., Gres, V., Kubasova, N., Morris, I., et al. (2017). Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med 23, 1309–1318.
Powley, T.L. (2000). Vagal input to the enteric nervous system. Gut 47, 30iv–32.
Rached, M.T., Kode, A., Silva, B.C., Jung, D.Y., Gray, S., Ong, H., Paik, J. H., DePinho, R.A., Kim, J.K., Karsenty, G., et al. (2010). FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 120, 357–368.
Rezai-Zadeh, K., Yu, S., Jiang, Y., Laque, A., Schwartzenburg, C., Morrison, C.D., Derbenev, A.V., Zsombok, A., and Münzberg, H. (2014). Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol Metab 3, 681–693.
Richards, P., Thornberry, N.A., and Pinto, S. (2021). The gut-brain axis: identifying new therapeutic approaches for type 2 diabetes, obesity, and related disorders. Mol Metab 46, 101175.
Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., Duncan, A.E., Kau, A.L., Griffin, N.W., Lombard, V., Henrissat, B., Bain, J.R., et al. (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341.
Riggs, B.L., Melton Iii, L.J., Robb, R.A., Camp, J.J., Atkinson, E.J., McDaniel, L., Amin, S., Rouleau, P.A., and Khosla, S. (2008). A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res 23, 205–214.
Riminucci, M., Collins, M.T., Fedarko, N.S., Cherman, N., Corsi, A., White, K.E., Waguespack, S., Gupta, A., Hannon, T., Econs, M.J., et al. (2003). FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112, 683–692.
Rogers, G.B., and Bruce, K.D. (2013). Challenges and opportunities for faecal microbiota transplantation therapy. Epidemiol Infect 141, 2235–2242.
Roozendaal, B., McEwen, B.S., and Chattarji, S. (2009). Stress, memory and the amygdala. Nat Rev Neurosci 10, 423–433.
Rosen, E.D., and Spiegelman, B.M. (2014). What we talk about when we talk about fat. Cell 156, 20–44.
Rowe, G.C., Vialou, V., Sato, K., Saito, H., Yin, M., Green, T.A., Lotinun, S., Kveiborg, M., Horne, W.C., Nestler, E.J., et al. (2012). Energy expenditure and bone formation share a common sensitivity to AP-1 transcription in the hypothalamus. J Bone Miner Res 27, 1649–1658.
Ruan, H.B., Dietrich, M.O., Liu, Z.W., Zimmer, M.R., Li, M.D., Singh, J.P., Zhang, K., Yin, R., Wu, J., Horvath, T.L., et al. (2014). O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159, 306–317.
Sabatakos, G., Rowe, G.C., Kveiborg, M., Wu, M., Neff, L., Chiusaroli, R., Philbrick, W.M., and Baron, R. (2008). Doubly truncated FosB isoform (Δ2ΔFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in ssteoblasts independent of intrinsic AP-1 activity. J Bone Miner Res 23, 584–595.
Saito, M., Okamatsu-Ogura, Y., Matsushita, M., Watanabe, K., Yoneshiro, T., Nio-Kobayashi, J., Iwanaga, T., Miyagawa, M., Kameya, T., Nakada, K., et al. (2009). High incidence of metabolically active brown adipose tissue in healthy adult humans. Diabetes 58, 1526–1531.
Sarkar, A., Lehto, S.M., Harty, S., Dinan, T.G., Cryan, J.F., and Burnet, P. W.J. (2016). Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neuroscis 39, 763–781.
Savignac, H.M., Corona, G., Mills, H., Chen, L., Spencer, J.P.E., Tzortzis, G., and Burnet, P.W.J. (2013). Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem Int 63, 756–764.
Savignac, H.M., Couch, Y., Stratford, M., Bannerman, D.M., Tzortzis, G., Anthony, D.C., and Burnet, P.W.J. (2016). Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice. Brain Behav Immun 52, 120–131.
Scarpace, P.J., and Matheny, M. (1998). Leptin induction of UCP1 gene expression is dependent on sympathetic innervation. Am J Physiol 275, E259–E264.
Scherer, P.E. (2016). The multifaceted roles of adipose tissue—therapeutic targets for diabetes and beyond: the 2015 Banting Lecture. Diabetes 65, 1452–1461.
Schneeberger, M., Parolari, L., Das Banerjee, T., Bhave, V., Wang, P., Patel, B., Topilko, T., Wu, Z., Choi, C.H.J., Yu, X., et al. (2019). Regulation of energy expenditure by brainstem GABA neurons. Cell 178, 672–685.e12.
Schulz, T.J., and Tseng, Y.H. (2013). Brown adipose tissue: development, metabolism and beyond. Biochem J 453, 167–178.
Sclafani, A., Marambaud, P., and Ackroff, K. (2014). Sucrose-conditioned flavor preferences in sweet ageusic T1r3 and Calhm1 knockout mice. Physiol Behav 126, 25–29.
Sender, R., Fuchs, S., and Milo, R. (2016). Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340.
Shabalina, I.G., Petrovic, N., de Jong, J.M.A., Kalinovich, A.V., Cannon, B., and Nedergaard, J. (2013). UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 5, 1196–1203.
Sharon, G., Cruz, N.J., Kang, D.W., Gandal, M.J., Wang, B., Kim, Y.M., Zink, E.M., Casey, C.P., Taylor, B.C., Lane, C.J., et al. (2019). Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177, 1600–1618.e17.
Sharp, L.Z., Shinoda, K., Ohno, H., Scheel, D.W., Tomoda, E., Ruiz, L., Hu, H., Wang, L., Pavlova, Z., Gilsanz, V., et al. (2012). Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE 7, e49452.
Shi, H., Song, C.K., Giordano, A., Cinti, S., and Bartness, T.J. (2005). Sensory or sympathetic white adipose tissue denervation differentially affects depot growth and cellularity. Am J Physiol Regul Integr Comp Physiol 288, R1028–R1037.
Shi, Y., Yadav, V.K., Suda, N., Liu, X.S., Guo, X.E., Myers Martin G. J., and Karsenty, G. (2008). Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci USA 105, 20529–20533.
Shi, Y.C., Lau, J., Lin, Z., Zhang, H., Zhai, L., Sperk, G., Heilbronn, R., Mietzsch, M., Weger, S., Huang, X.F., et al. (2013). Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 17, 236–248.
Shibata, H., and Bukowiecki, L.J. (1987). Regulatory alterations of daily energy expenditure induced by fasting or overfeeding in unrestrained rats. J Appl Physiol 63, 465–470.
Shinoda, K., Luijten, I.H.N., Hasegawa, Y., Hong, H., Sonne, S.B., Kim, M., Xue, R., Chondronikola, M., Cypess, A.M., Tseng, Y.H., et al. (2015). Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med 21, 389–394.
Shultz, S.R., MacFabe, D.F., Ossenkopp, K.P., Scratch, S., Whelan, J., Taylor, R., and Cain, D.P. (2008). Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology 54, 901–911.
Sidossis, L., and Kajimura, S. (2015). Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 125, 478–486.
Slavin, B.G., and Ballard, K.W. (1978). Morphological studies on the adrenergic innervation of white adipose tissue. Anat Rec 191, 377–389.
Slykerman, R.F., Hood, F., Wickens, K., Thompson, J.M.D., Barthow, C., Murphy, R., Kang, J., Rowden, J., Stone, P., Crane, J., et al. (2017). Effect of lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: a randomised double-blind placebo-controlled trial. Ebiomedicine 24, 159–165.
Song, C.K., Schwartz, G.J., and Bartness, T.J. (2009). Anterograde transneuronal viral tract tracing reveals central sensory circuits from white adipose tissue. Am J Physiol Regul Integr Comp Physiol 296, R501–R511.
Song, K., Wang, H., Kamm, G.B., Pohle, J., Reis, F.C., Heppenstall, P., Wende, H., and Siemens, J. (2016). The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 353, 1393–1398.
Spitz, J., Hecht, G., Taveras, M., Aoys, E., and Alverdy, J. (1994). The effect of dexamethasone administration on rat intestinal permeability: the role of bacterial adherence. Gastroenterology 106, 35–41.
Ste. Marie, L., Miura, G.I., Marsh, D.J., Yagaloff, K., and Palmiter, R.D. (2000). A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 97, 12339–12344.
Stephenson, M., and Rowatt, E. (1947). The production of acetylcholine by a strain of Lactobacillus plantarum. J Gen Microbiol 1, 279–298.
Sternbach, H., and State, R. (1997). Antibiotics: neuropsychiatric effects and psychotropic interactions. Harvard Rev Psychiatry 5, 214–226.
Strandwitz, P., Kim, K.H., Terekhova, D., Liu, J.K., Sharma, A., Levering, J., McDonald, D., Dietrich, D., Ramadhar, T.R., Lekbua, A., et al. (2019). GABA-modulating bacteria of the human gut microbiota. Nat Microbiol 4, 396–403.
Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.N., Kubo, C., and Koga, Y. (2004). Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558, 263–275.
Sun, L., Tamma, R., Yuen, T., Colaianni, G., Ji, Y., Cuscito, C., Bailey, J., Dhawan, S., Lu, P., Calvano, C.D., et al. (2016). Functions of vasopressin and oxytocin in bone mass regulation. Proc Natl Acad Sci USA 113, 164–169.
Szymusiak, R., and Satinoff, E. (1982). Acute thermoregulatory effects of unilateral electrolytic lesions of the medial and lateral preoptic area in rats. Physiol Behav 28, 161–170.
Tabarean, I.V. (2021). Activation of preoptic arginine vasopressin neurons induces hyperthermia in male mice. Endocrinology 162.
Takahashi, T.M., Sunagawa, G.A., Soya, S., Abe, M., Sakurai, K., Ishikawa, K., Yanagisawa, M., Hama, H., Hasegawa, E., Miyawaki, A., et al. (2020). A discrete neuronal circuit induces a hibernation-like state in rodents. Nature 583, 109–114.
Takeda, S., Elefteriou, F., Levasseur, R., Liu, X., Zhao, L., Parker, K.L., Armstrong, D., Ducy, P., and Karsenty, G. (2002). Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317.
Tamma, R., Colaianni, G., Zhu, L., DiBenedetto, A., Greco, G., Montemurro, G., Patano, N., Strippoli, M., Vergari, R., Mancini, L., et al. (2009). Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci USA 106, 7149–7154.
Tamma, R., Sun, L., Cuscito, C., Lu, P., Corcelli, M., Li, J., Colaianni, G., Moonga, S.S., Di Benedetto, A., Grano, M., et al. (2013). Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc Natl Acad Sci USA 110, 18644–18649.
Tan, C.L., Cooke, E.K., Leib, D.E., Lin, Y.C., Daly, G.E., Zimmerman, C. A., and Knight, Z.A. (2016). Warm-sensitive neurons that control body temperature. Cell 167, 47–59.e15.
Tan, C.L., and Knight, Z.A. (2018). Regulation of body temperature by the nervous system. Neuron 98, 31–48.
Tan, H.E., Sisti, A.C., Jin, H., Vignovich, M., Villavicencio, M., Tsang, K. S., Goffer, Y., and Zuker, C.S. (2020). The gut-brain axis mediates sugar preference. Nature 580, 511–516.
Thomas, C.M., Hong, T., van Pijkeren, J.P., Hemarajata, P., Trinh, D.V., Hu, W., Britton, R.A., Kalkum, M., and Versalovic, J. (2012). Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS ONE 7, e31951.
Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B., et al. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144, 1394–1401.e4.
Timmerman, R.J., Thompson, J., Noordzij, H.M., and van der Meer, J.W. (1992). Psychogenic periodic fever. Neth J Med 41, 158–160.
Todd, A.J. (2010). Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11, 823–836.
Tsavkelova, E.A., Botvinko, I.V., Kudrin, V.S., and Oleskin, A.V. (2000). Detection of neurotransmitter amines in microorganisms with the use of high-performance liquid chromatography. Dokl Biochem 372, 115–117.
Tschöp, M.H., Speakman, J.R., Arch, J.R.S., Auwerx, J., Brüning, J.C., Chan, L., Eckel, R.H., FareseJr, R.V., Galgani, J.E., Hambly, C., et al. (2011). A guide to analysis of mouse energy metabolism. Nat Methods 9, 57–63.
Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R., and Gordon, J.I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031.
Ulrich-Lai, Y.M., Fulton, S., Wilson, M., Petrovich, G., and Rinaman, L. (2015). Stress exposure, food intake and emotional state. Stress 18, 381–399.
Ulrich-Lai, Y.M., and Ryan, K.K. (2014). Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications. Cell Metab 19, 910–925.
Unsal, H., Balkaya, M., Unsal, C., Biyik, H., Başbülbül, G., and Poyrazoğlu, E. (2008). The short-term effects of different doses of dexamethasone on the numbers of some bacteria in the ileum. Dig Dis Sci 53, 1842–1845.
van de Wouw, M., Boehme, M., Lyte, J.M., Wiley, N., Strain, C., O’Sullivan, O., Clarke, G., Stanton, C., Dinan, T.G., and Cryan, J.F. (2018). Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol 596, 4923–4944.
van Marken Lichtenbelt, W.D., Vanhommerig, J.W., Smulders, N.M., Drossaerts, J.M.A.F.L., Kemerink, G.J., Bouvy, N.D., Schrauwen, P., and Teule, G.J.J. (2009). Cold-activated brown adipose tissue in healthy men. N Engl J Med 360, 1500–1508.
Vaughan, C.H., and Bartness, T.J. (2012). Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses. Am J Physiol Regul Integr Comp Physiol 302, R1049–R1058.
Vegiopoulos, A., Müller-Decker, K., Strzoda, D., Schmitt, I., Chichelnitskiy, E., Ostertag, A., Berriel Diaz, M., Rozman, J., Hrabe de Angelis, M., Nüsing, R.M., et al. (2010). Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161.
Virtanen, K.A., Lidell, M.E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N.J., Enerbäck, S., et al. (2009). Functional brown adipose tissue in healthy adults. N Engl J Med 360, 1518–1525.
Vogt, N.M., Kerby, R.L., Dill-McFarland, K.A., Harding, S.J., Merluzzi, A. P., Johnson, S.C., Carlsson, C.M., Asthana, S., Zetterberg, H., Blennow, K., et al. (2017). Gut microbiome alterations in Alzheimer’s disease. Sci Rep 7, 13537.
Walejko, J.M., Kim, S., Goel, R., Handberg, E.M., Richards, E.M., Pepine, C.J., and Raizada, M.K. (2018). Gut microbiota and serum metabolite differences in African Americans and White Americans with high blood pressure. Int J Cardiol 271, 336–339.
Wang, P., Loh, K.H., Wu, M., Morgan, D.A., Schneeberger, M., Yu, X., Chi, J., Kosse, C., Kim, D., Rahmouni, K., et al. (2020). A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583, 839–844.
Wang, T.A., Teo, C.F., Åkerblom, M., Chen, C., Tynan-La Fontaine, M., Greiner, V.J., Diaz, A., McManus, M.T., Jan, Y.N., and Jan, L.Y. (2019). Thermoregulation via temperature-dependent PGD2 production in mouse preoptic area. Neuron 103, 309–322.e7.
Wang, X.F., Liu, J.J., Xia, J., Liu, J., Mirabella, V., and Pang, Z.P. (2015). Endogenous glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Rep 12, 726–733.
Wang, Y., and Kasper, L.H. (2014). The role of microbiome in central nervous system disorders. Brain Behav Immun 38, 1–12.
Waterson, M.J., and Horvath, T.L. (2015). Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell Metab 22, 962–970.
Westfall, S., Lomis, N., Kahouli, I., Dia, S.Y., Singh, S.P., and Prakash, S. (2017). Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci 74, 3769–3787.
Whitehead, W.E., Palsson, O., and Jones, K.R. (2002). Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology 122, 1140–1156.
Wiedmann, N.M., Stefanidis, A., and Oldfield, B.J. (2017). Characterization of the central neural projections to brown, white, and beige adipose tissue. FASEB J 31, 4879–4890.
Willesen, M.G., Kristensen, P., and Rømer, J. (1999). Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316.
Williams, E.K., Chang, R.B., Strochlic, D.E., Umans, B.D., Lowell, B.B., and Liberles, S.D. (2016). Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166, 209–221.
Wirsen, C. (1964). Adrenergic innervation of sdipose tissue examined by fluorescence microscopy. Nature 202, 913.
Wu, J., Boström, P., Sparks, L.M., Ye, L., Choi, J.H., Giang, A.H., Khandekar, M., Virtanen, K.A., Nuutila, P., Schaart, G., et al. (2012). Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376.
Xiao, W., Jiao, Z.L., Senol, E., Yao, J., Zhao, M., Zhao, Z.D., Chen, X., Cao, P., Fu, Y., Gao, Z., et al. (2022). Neural circuit control of innate behaviors. Sci China Life Sci 65, 466–499.
Xu, B., and Xie, X. (2016). Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci 17, 282–292.
Xu, J., Bartolome, C.L., Low, C.S., Yi, X., Chien, C.H., Wang, P., and Kong, D. (2018). Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509.
Xu, R., Wu, B., Liang, J., He, F., Gu, W., Li, K., Luo, Y., Chen, J., Gao, Y., Wu, Z., et al. (2020). Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav Immun 85, 120–127.
Xue, Y., Petrovic, N., Cao, R., Larsson, O., Lim, S., Chen, S., Feldmann, H. M., Liang, Z., Zhu, Z., Nedergaard, J., et al. (2009). Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab 9, 99–109.
Yadav, V.K., Oury, F., Suda, N., Liu, Z.W., Gao, X.B., Confavreux, C., Klemenhagen, K.C., Tanaka, K.F., Gingrich, J.A., Guo, X.E., et al. (2009). A Serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138, 976–989.
Yan, Q.W., Yang, Q., Mody, N., Graham, T.E., Hsu, C.H., Xu, Z., Houstis, N.E., Kahn, B.B., and Rosen, E.D. (2007). The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes 56, 2533–2540.
Yang, F., Liu, Y., Chen, S., Dai, Z., Yang, D., Gao, D., Shao, J., Wang, Y., Wang, T., Zhang, Z., et al. (2020a). A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss. J Clin Invest 130, 6539–6554.
Yang, W.Z., Du, X., Zhang, W., Gao, C., Xie, H., Xiao, Y., Jia, X., Liu, J., Xu, J., Fu, X., et al. (2020b). Parabrachial neuron types categorically encode thermoregulation variables during heat defense. Sci Adv 6, eabb9414.
Yang, X., and Ruan, H.B. (2015). Neuronal control of adaptive thermogenesis. Front Endocrinol 6, 149.
Yano, J.M., Yu, K., Donaldson, G.P., Shastri, G.G., Ann, P., Ma, L., Nagler, C.R., Ismagilov, R.F., Mazmanian, S.K., and Hsiao, E.Y. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276.
Yasuda, T., Masaki, T., Kakuma, T., and Yoshimatsu, H. (2004). Hypothalamic melanocortin system regulates sympathetic nerve activity in brown adipose tissue. Exp Biol Med 229, 235–239.
Yi, C.X., la Fleur, S.E., Fliers, E., and Kalsbeek, A. (2010). The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim Biophys Acta 1802, 416–431.
Yokotani, K., Muramatsu, I., and Fujiwara, M. (1983). Effects of the sympathetic nervous system on bethanechol-induced elevation of gastric acid secretion and mucosal blood flow in rats. J Pharmacol Exp Ther 227, 478–483.
Yoneshiro, T., Aita, S., Matsushita, M., Kayahara, T., Kameya, T., Kawai, Y., Iwanaga, T., and Saito, M. (2013). Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123, 3404–3408.
Yoneshiro, T., Matsushita, M., Nakae, S., Kameya, T., Sugie, H., Tanaka, S., and Saito, M. (2016). Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans. Am J Physiol Regul Integr Comp Physiol 310, R999–R1009.
Yoshida, K., Li, X., Cano, G., Lazarus, M., and Saper, C.B. (2009). Parallel preoptic pathways for thermoregulation. J Neurosci 29, 11954–11964.
Yoshikawa, Y., Kode, A., Xu, L., Mosialou, I., Silva, B.C., Ferron, M., Clemens, T.L., Economides, A.N., and Kousteni, S. (2011). Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. J Bone Miner Res 26, 2012–2025.
Young, P., Arch, J.R.S., and Ashwell, M. (1984). Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett 167, 10–14.
Youngstrom, T.G., and Bartness, T.J. (1995). Catecholaminergic innervation of white adipose tissue in Siberian hamsters. Am J Physiol 268, R744–R751.
Yu, S., Cheng, H., François, M., Qualls-Creekmore, E., Huesing, C., He, Y., Jiang, Y., Gao, H., Xu, Y., Zsombok, A., et al. (2018). Preoptic leptin signaling modulates energy balance independent of body temperature regulation. elife 7, e33505.
Yu, S., Qualls-Creekmore, E., Rezai-Zadeh, K., Jiang, Y., Berthoud, H.R., Morrison, C.D., Derbenev, A.V., Zsombok, A., and Münzberg, H. (2016). Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. J Neurosci 36, 5034–5046.
Yuan, F., Jiang, H., Yin, H., Jiang, X., Jiao, F., Chen, S., Ying, H., Chen, Y., Zhai, Q., and Guo, F. (2020). Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation. Nat Commun 11, 2847.
Yuan, N., Chen, Y., Xia, Y., Dai, J., and Liu, C. (2019). Inflammationrelated biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl Psychiatry 9, 233.
Zeng, W., Pirzgalska, R.M., Pereira, M.M.A., Kubasova, N., Barateiro, A., Seixas, E., Lu, Y.H., Kozlova, A., Voss, H., Martins, G.G., et al. (2015). Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94.
Zeng, X., Ye, M., Resch, J.M., Jedrychowski, M.P., Hu, B., Lowell, B.B., Ginty, D.D., and Spiegelman, B.M. (2019). Innervation of thermogenic adipose tissue via a calsyntenin 3β-S100b axis. Nature 569, 229–235.
Zhan, C., Zhou, J., Feng, Q., Zhang, J.E., Lin, S., Bao, J., Wu, P., and Luo, M. (2013). Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J Neurosci 33, 3624–3632.
Zhang, W., Sunanaga, J., Takahashi, Y., Mori, T., Sakurai, T., Kanmura, Y., and Kuwaki, T. (2010). Orexin neurons are indispensable for stress-induced thermogenesis in mice. J Physiol 588, 4117–4129.
Zhang, Y., Kerman, I.A., Laque, A., Nguyen, P., Faouzi, M., Louis, G.W., Jones, J.C., Rhodes, C., and Münzberg, H. (2011). Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci 31, 1873–1884.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
Zhang, Z., Reis, F.M.C.V., He, Y., Park, J.W., DiVittorio, J.R., Sivakumar, N., van Veen, J.E., Maesta-Pereira, S., Shum, M., Nichols, I., et al. (2020). Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice. Nat Commun 11, 6378.
Zhao, Z.D., Yang, W.Z., Gao, C., Fu, X., Zhang, W., Zhou, Q., Chen, W., Ni, X., Lin, J.K., Yang, J., et al. (2017). A hypothalamic circuit that controls body temperature. Proc Natl Acad Sci USA 114, 2042–2047.
Zheng, P., Wu, J., Zhang, H., Perry, S.W., Yin, B., Tan, X., Chai, T., Liang, W., Huang, Y., Li, Y., et al. (2021). The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression. Mol Psychiatry 26, 2380–2392.
Zheng, P., Zeng, B., Liu, M., Chen, J., Pan, J., Han, Y., Liu, Y., Cheng, K., Zhou, C., Wang, H., et al. (2019). The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv 5, eaau8317.
Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., et al. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 21, 786–796.
Zingaretti, M.C., Crosta, F., Vitali, A., Guerrieri, M., Frontini, A., Cannon, B., Nedergaard, J., and Cinti, S. (2009). The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23, 3113–3120.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (31822026, 31822018, 31770936, 82072489, 32122039), the National Key R&D Program of China (2017YFA0205903, 2017YFA0505800, 2021ZD020390), the Key Research Program of Frontier Sciences of Chinese Academy of Sciences (QYZDB-SSW-SMC056), Beijing Natural Science Foundation (5222010), and the Tsinghua University (School of Medicine)-Xiamen Changgeng Hospital Co. Ltd. Joint Research Center for Anaphylactic Disease.
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Zeng, W., Yang, F., Shen, W.L. et al. Interactions between central nervous system and peripheral metabolic organs. Sci. China Life Sci. 65, 1929–1958 (2022). https://doi.org/10.1007/s11427-021-2103-5
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DOI: https://doi.org/10.1007/s11427-021-2103-5