Skip to main content

Advertisement

SpringerLink
Log in

Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner

  • ORIGINAL ARTICLE
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Evidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus, orexigenic agouti–related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons, we used mice with the AgRP-specific GHR deletion (AgRPΔGHR). We found that female AgRPΔGHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10 °C, 22 °C, or 30 °C, compared to control mice. Low body core temperature in female AgRPΔGHR mice has been associated with significant reductions in Ucp1 and Pgc1α expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRPΔGHR female mice, while the number of Fos+ AgRP neurons was increased in female controls exposed to cold. Global transcriptome from BAT identified increased the expression of genes related to immune responses and chemokine activity and decreased the expression of genes involved in triglyceride synthesis and metabolic pathways in AgRPΔGHR female mice. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRPΔGHR animals. Collectively, these data demonstrate a novel sex-specific role for GHR signaling in AgRP neurons in thermal regulation, which might be particularly relevant during aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AgRP:

Agouti-related peptide

ARC:

Arcuate nucleus

BAT:

Brown adipose tissue

CNS:

Central nervous system

DMH:

Dorsomedial hypothalamic nucleus

GH:

Growth hormone

GHR:

Growth hormone receptor

GHRH:

Growth hormone–releasing hormone

LHA:

Lateral hypothalamus

POMC:

Proopiomelanocortin

PVH:

Paraventricular hypothalamic nucleus

References

  1. Mattson MP. Perspective: does brown fat protect against diseases of aging? Ageing Res Rev. 2010;9(1):69–76.

    Article  CAS  PubMed  Google Scholar 

  2. Roh E, Kim MS. Brain regulation of energy metabolism. Endocrinol Metab (Seoul). 2016;31(4):519–24.

    Article  CAS  PubMed  Google Scholar 

  3. Robertson SA, Leinninger GM, Myers MG Jr. Molecular and neural mediators of leptin action. Physiol Behav. 2008;94(5):637–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Belgardt BF, Bruning JC. CNS leptin and insulin action in the control of energy homeostasis. Ann N Y Acad Sci. 2010;1212:97–113.

    Article  CAS  PubMed  Google Scholar 

  5. Van Someren EJ. Thermoregulation and aging. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R99-102.

    Article  PubMed  Google Scholar 

  6. Osilla EV, JL Marsidi, S Sharma, Physiology, temperature regulation. StatPearls. 2022: Treasure Island (FL).

  7. Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. Int J Obes (Lond). 2010;34(Suppl 1):S47-55.

    Article  PubMed  Google Scholar 

  8. Chong AC, Greendyk RA, Zeltser LM. Distinct networks of leptin- and insulin-sensing neurons regulate thermogenic responses to nutritional and cold challenges. Diabetes. 2015;64(1):137–46.

    Article  CAS  PubMed  Google Scholar 

  9. Han Y, et al. Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding. Nat Commun. 2021;12(1):3525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu S, et al. The hypothalamic preoptic area and body weight control. Neuroendocrinol. 2018;106(2):187–94.

    Article  CAS  Google Scholar 

  11. Kuperman Y, et al. CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. Cell Metab. 2016;23(6):1185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol. 2004;63:189–225.

    Article  CAS  PubMed  Google Scholar 

  13. Waters MJ, et al. New insights into growth hormone action. J Mol Endocrinol. 2006;36(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  14. Darcy J, et al. Brown adipose tissue function is enhanced in long-lived, male Ames dwarf mice. Endocrinol. 2016;157(12):4744–53.

    Article  CAS  Google Scholar 

  15. Darcy J, et al. Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice. Aging (Albany NY). 2018;10(10):2709–22.

    Article  CAS  PubMed  Google Scholar 

  16. Westbrook R, et al. Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice. J Gerontol A Biol Sci Med Sci. 2009;64(4):443–51.

    Article  PubMed  Google Scholar 

  17. Furigo IC, et al. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. Nat Commun. 2019;10(1):662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Lima JBM, et al. Hypothalamic GHR-SIRT1 axis in fasting. Cells. 2021; 10(4).

  19. List EO, et al. Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. Endocrinol. 2014;155(5):1793–805.

    Article  Google Scholar 

  20. Sadagurski M, Cady G, Miller RA. Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell. 2017;16(4):652–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sadagurski M, et al. Human IL6 enhances leptin action in mice. Diabetologia. 2010;53(3):525–35.

    Article  CAS  PubMed  Google Scholar 

  22. Schneider A, et al. Growth hormone signaling shapes the impact of environmental temperature on transcriptomic profile of different adipose tissue depots in male mice. J Gerontol: Series A. 2021;77(5):941–6.

    Article  Google Scholar 

  23. Sanchez-Alavez M, Alboni S, Conti B. Sex- and age-specific differences in core body temperature of C57Bl/6 mice. Age (Dordr). 2011;33(1):89–99.

    Article  CAS  PubMed  Google Scholar 

  24. Klein Hazebroek M, Keipert S. Adapting to the cold: a role for endogenous fibroblast growth factor 21 in thermoregulation? Front Endocrinol (Lausanne). 2020;11:389.

    Article  PubMed  Google Scholar 

  25. Deem JD, et al. Cold-induced hyperphagia requires AgRP neuron activation in mice. Elife. 2020;9.

  26. Zimmer MR, et al. Functional ontogeny of hypothalamic Agrp neurons in neonatal mouse behaviors. Cell. 2019;178(1):44–59 (e7).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Timper K, Bruning JC. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech. 2017;10(6):679–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Lima JBM, et al. ARCGHR neurons regulate muscle glucose uptake. Cells. 2021;10(5):1093.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Furigo IC, et al. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons. FASEB J. 2019; fj201901315R.

  30. Wasinski F, et al. Growth hormone receptor deletion reduces the density of axonal projections from hypothalamic arcuate nucleus neurons. Neurosci. 2020;434:136–47.

    Article  CAS  Google Scholar 

  31. Dietrich MO, et al. Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell. 2015;160(6):1222–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cavalcanti-de-Albuquerque JP, et al. Regulation of substrate utilization and adiposity by Agrp neurons. Nat Commun. 2019;10(1):311.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Graja A, Schulz TJ. Mechanisms of aging-related impairment of brown adipocyte development and function. Gerontol. 2015;61(3):211–7.

    Article  Google Scholar 

  34. Burke LK, et al. mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice. Elife. 2017;6.

  35. Dominick G, et al. Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. Endocrinol. 2015;156(2):565–75.

    Article  Google Scholar 

  36. Campbell JN, et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci. 2017;20(3):484–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shi H, et al. Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis. Am J Physiol Endocrinol Metab. 2008;294(3):E630–9.

    Article  CAS  PubMed  Google Scholar 

  38. van de Wall E, et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinol. 2008;149(4):1773–85.

    Article  Google Scholar 

  39. Leung KC, et al. Estrogen regulation of growth hormone action. Endocr Rev. 2004;25(5):693–721.

    Article  CAS  PubMed  Google Scholar 

  40. Olofsson LE, Pierce AA, Xu AW. Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake. Proc Natl Acad Sci U S A. 2009;106(37):15932–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kruijver FP, Swaab DF. Sex hormone receptors are present in the human suprachiasmatic nucleus. Neuroendocrinol. 2002;75(5):296–305.

    Article  CAS  Google Scholar 

  42. Morselli LL, et al. Control of energy expenditure by AgRP neurons of the arcuate nucleus: neurocircuitry, signaling pathways, and angiotensin. Curr Hypertens Rep. 2018;20(3):25.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Yan C, Chen J, Chen N. Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. Sci Rep. 2016;6:22640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang X, et al. Regulation of ANKRD9 expression by lipid metabolic perturbations. BMB Rep. 2009;42(9):568–73.

    Article  CAS  PubMed  Google Scholar 

  45. Yu XH, et al. LncRNA kcnq1ot1 promotes lipid accumulation and accelerates atherosclerosis via functioning as a ceRNA through the miR-452-3p/HDAC3/ABCA1 axis. Cell Death Dis. 2020;11(12):1043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ghimire S, Kim J. PEG3 controls lipogenesis through ACLY. PLoS One. 2021;16(5):e0252354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alshahrani S, et al. Increased Slc12a1 expression in beta-cells and improved glucose disposal in Slc12a2 heterozygous mice. J Endocrinol. 2015;227(3):153–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Flowers MT, Ntambi JM. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol. 2008;19(3):248–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee SH, et al. Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment. J Lipid Res. 2004;45(9):1674–82.

    Article  CAS  PubMed  Google Scholar 

  50. Tran LT, et al. Hypothalamic control of energy expenditure and thermogenesis. Exp Mol Med. 2022;54(4):358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yasuda T, et al. Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci Lett. 2003;349(2):75–8.

    Article  CAS  PubMed  Google Scholar 

  52. Nelson CN, et al. Growth hormone activated STAT5 is required for induction of beige fat in vivo. Growth Horm IGF Res. 2018;42–43:40–51.

    Article  PubMed  Google Scholar 

  53. Li Y, Knapp JR, Kopchick JJ. Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med (Maywood). 2003;228(2):207–15.

    Article  CAS  PubMed  Google Scholar 

  54. Desai BN, Harris RB. Integrated effects of leptin in the forebrain and hindbrain of male rats. Endocrinol. 2013;154(8):2663–75.

    Article  CAS  Google Scholar 

  55. Hunter WS, et al. Low body temperature in long-lived Ames dwarf mice at rest and during stress. Physiol Behav. 1999;67(3):433–7.

    Article  CAS  PubMed  Google Scholar 

  56. Hauck SJ, et al. Reduced levels of thyroid hormones, insulin, and glucose, and lower body core temperature in the growth hormone receptor/binding protein knockout mouse. Exp Biol Med (Maywood). 2001;226(6):552–8.

    Article  CAS  PubMed  Google Scholar 

  57. Conti B, et al. Transgenic mice with a reduced core body temperature have an increased life span. Science. 2006;314(5800):825–8.

    Article  CAS  PubMed  Google Scholar 

  58. Waalen J, Buxbaum JN. Is older colder or colder older? The association of age with body temperature in 18,630 individuals. J Gerontol A Biol Sci Med Sci. 2011;66(5):487–92.

    Article  PubMed  Google Scholar 

  59. Yanovich R, Ketko I, Charkoudian N. Sex differences in human thermoregulation: relevance for 2020 and beyond. Physiol. 2020;35(3):177–84.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the American Diabetes Association grant #1-lB-IDF-063, a Feasibility Grant from the Michigan Diabetes Research Center (P30DK020572) NIDDK, and MICP Core and metabolic core (P30DK020572) NIDDK and WSU funds for MS. LK was supported by NIH 5T32GM14519-01, and LS was supported by NIH 5T32HL120822-09.

Author information

Author notes

  1. Lukas Stilgenbauer and Juliana Bezerra Medeiros de Lima contributed equally to this study.

Authors and Affiliations

  1. Department of Biological Sciences, Integrative Biosciences Center (IBio), Wayne State University, 6135 Woodward, Detroit, MI, 48202, USA

    Lukas Stilgenbauer, Juliana Bezerra Medeiros de Lima, Lucas Kniess Debarba, Manal Khan, Lisa Koshko & Marianna Sadagurski

  2. Edison Biotechnology Institute, Ohio University, Athens, OH, USA

    John J. Kopchick

  3. Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA

    Andrzej Bartke

  4. Nutrition College, Federal University of Pelotas, Pelotas, Rio Grande Do Sul, Brazil

    Augusto Schneider

Authors
  1. Lukas Stilgenbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juliana Bezerra Medeiros de Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucas Kniess Debarba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manal Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lisa Koshko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John J. Kopchick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrzej Bartke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Augusto Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marianna Sadagurski
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LS, JBML, and LKD carried out the research and reviewed the manuscript. MK and LK assisted in the data collection and experimental design. JJK contributed the GHR floxed mice. AS and AB analyzed the data and reviewed the manuscript. MS designed the study, analyzed the data, wrote the manuscript, and is responsible for the integrity of this work. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Marianna Sadagurski.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 31 KB)

Supplementary file2 (DOCX 621 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stilgenbauer, L., de Lima, J.B.M., Debarba, L.K. et al. Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner. GeroScience 45, 1745–1759 (2023). https://doi.org/10.1007/s11357-023-00726-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-023-00726-4

Keywords

Search

Navigation