Skip to main content
Log in

Estrogens, inflammation and obesity: an overview

  • Review
  • Published:
Frontiers in Biology

Abstract

Emerging research has suggested that inflammatory stress may play a role in the development of obesity. Both the leptin and insulin receptor are sensitive to intracellular inflammatory signaling that can be stimulated through toll-like receptor 4 activation by saturated fat. Pharmacological intervention within this cascade often protects animals from becoming obese, thus highlighting inflammatory pathways as a possible site of study in the prevention of pathologic weight gain. It has been well established in animal models that females display a marked reduction in the susceptibility to weight gain on high-fat diets compared to males. In addition, it has been widely accepted that females are partially protected from inflammatory-related diseases. At the molecular level, this reduction in disease susceptibility has been suggested to be due to the anti-inflammatory properties of 17 β-estradiol. Through direct free radical scavenging, transcriptional regulation, and protein interactions, chronic exposure to estradiol can reduce systemic inflammatory stress. As the knowledge base continues to grow on the etiology of obesity, further research is needed on the precise molecular pathways that can be inhibited by estradiol. Understanding of such pathways may provide a basis for the future use of estrogen and its related compounds (daidzein, genistein, resveratrol) to prevent weight gain in peri- and post-menopausal females.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Anand B K, Brobeck J R (1951). Hypothalamic control of food intake in rats and cats. Yale J Biol Med, 24(2): 123–140

    PubMed  CAS  Google Scholar 

  • Basterfield L, Lumley L K, Mathers J C (2009). Wheel running in female C57BL/6J mice: impact of oestrus and dietary fat and effects on sleep and body mass. Int J Obes (Lond), 33(2): 212–218

    Article  CAS  Google Scholar 

  • Berthoud H R, Morrison C (2008). The brain, appetite, and obesity. Annu Rev Psychol, 59(1): 55–92

    Article  PubMed  Google Scholar 

  • Boghossian S, Lemmon K, Park M, York D A (2009). High-fat diets induce a rapid loss of the insulin anorectic response in the amygdala. Am J Physiol Regul Integr Comp Physiol, 297(5): R1302–R1311

    Article  PubMed  CAS  Google Scholar 

  • Bryzgalova G, Lundholm L, Portwood N, Gustafsson J A, Khan A, Efendic S, Dahlman-Wright K (2008). Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat dietfed mice. Am J Physiol Endocrinol Metab, 295(4): E904–E912

    Article  PubMed  CAS  Google Scholar 

  • Chadwick C C, Chippari S, Matelan E, Borges-Marcucci L, Eckert A M, Keith J C Jr, Albert L M, Leathurby Y, Harris H A, Bhat R A, Ashwell M, Trybulski E, Winneker R C, Adelman S J, Steffan R J, Harnish D C (2005). Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity. Proc Natl Acad Sci USA, 102(7): 2543–2548

    Article  PubMed  CAS  Google Scholar 

  • Charradi K, Sebai H, Elkahoui S, Ben Hassine F, Limam F, Aouani E (2011). Grape seed extract alleviates high-fat diet-induced obesity and heart dysfunction by preventing cardiac siderosis. Cardiovasc Toxicol, 11(1): 28–37

    Article  PubMed  Google Scholar 

  • Clegg D J, Brown L M, Woods S C, Benoit S C (2006). Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes, 55(4): 978–987

    Article  PubMed  CAS  Google Scholar 

  • Clegg D J, Gotoh K, Kemp C, Wortman M D, Benoit S C, Brown L M, D’Alessio D, Tso P, Seeley R J, Woods S C (2011). Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav, 103(1): 10–16

    Article  PubMed  CAS  Google Scholar 

  • Clegg D J, S C Woods (2004). The physiology of obesity. Clin Obstet Gynecol, 47(4): 967–979; discussion 980–961

    Article  PubMed  Google Scholar 

  • Couse J F, Lindzey J, Grandien K, Gustafsson J A, Korach K S (1997). Tissue distribution and quantitative analysis of estrogen receptoralpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology, 138(11): 4613–4621

    Article  PubMed  CAS  Google Scholar 

  • Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G (2011). Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology, 54(1): 133–144

    Article  PubMed  CAS  Google Scholar 

  • Davis J E, Gabler N K, Walker-Daniels J, Spurlock M E (2008). Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring), 16(6): 1248–1255

    Article  CAS  Google Scholar 

  • De Souza C T, Araujo E P, Bordin S, Ashimine R, Zollner R L, Boschero A C, Saad M J, Velloso L A (2005). Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology, 146(10): 4192–4199

    Article  PubMed  Google Scholar 

  • Enriori P J, Evans A E, Sinnayah P, Cowley M A (2006). Leptin resistance and obesity. Obesity (Silver Spring), 14(Suppl 5): 254S–258S

    Article  CAS  Google Scholar 

  • Evans M J, Eckert A, Lai K, Adelman S J, Harnish D C (2001). Reciprocal antagonism between estrogen receptor and NF-kappaB activity in vivo. Circ Res, 89(9): 823–830

    Article  PubMed  CAS  Google Scholar 

  • Fazeli M, Zarkesh-Esfahani S H, et al(2004). Effects of Estrogen on Leptin Signaling and Leptin-induced TNF-alpha Production. British Endocrine Societies, Brighton, UK, BioScientifica.

    Google Scholar 

  • Ghisletti S, Meda C, Maggi A, Vegeto E (2005). 17beta-estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization. Mol Cell Biol, 25(8): 2957–2968

    Article  PubMed  CAS  Google Scholar 

  • Gong L, Yao F, Hockman K, Heng H H, Morton G J, Takeda K, Akira S, Low M J, Rubinstein M, MacKenzie R G (2008). Signal transducer and activator of transcription-3 is required in hypothalamic agoutirelated protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology, 149(7): 3346–3354

    Article  PubMed  CAS  Google Scholar 

  • Gonzales A M, Orlando R A (2008). Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes. Nutr Metab (Lond), 5(1): 17

    Article  Google Scholar 

  • Hamilton K L, Lin L, Wang Y, Knowlton A A (2007). Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression. Physiol Genomics, 32(2): 254–263

    Article  PubMed  Google Scholar 

  • Harris H A, Albert L M, Leathurby Y, Malamas M S, Mewshaw R E, Miller C P, Kharode Y P, Marzolf J, Komm B S, Winneker R C, Frail D E, Henderson R A, Zhu Y, Keith J C Jr (2003). Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology, 144(10): 4241–4249

    Article  PubMed  CAS  Google Scholar 

  • Haslam D W, James W P (2005). Obesity. Lancet, 366(9492): 1197–1209

    Article  PubMed  Google Scholar 

  • Hetherington R, Ranson S (1940). Hypothalamic lesions and adiposity in the rat. Anat Rec, 78(2): 149–172

    Article  Google Scholar 

  • Hewitt K N, Pratis K, Jones M E, Simpson E R (2003). Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology, 145(4): 1842–1848

    Article  PubMed  Google Scholar 

  • Hong J, Stubbins R E, Smith R R, Harvey A E, Núñez N P (2009). Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J, 8(1): 11

    Article  PubMed  Google Scholar 

  • Hotamisligil G S (2006). Inflammation and metabolic disorders. Nature, 444(7121): 860–867

    Article  PubMed  CAS  Google Scholar 

  • Jayaprakasam B, Olson L K, Schutzki R E, Tai M H, Nair M G (2006). Amelioration of obesity and glucose intolerance in high-fat-fed C57BL/6 mice by anthocyanins and ursolic acid in Cornelian cherry (Cornus mas). J Agric Food Chem, 54(1): 243–248

    Article  PubMed  CAS  Google Scholar 

  • Kahn B B, Flier J S (2000). Obesity and insulin resistance. J Clin Invest, 106(4): 473–481

    Article  PubMed  CAS  Google Scholar 

  • Kalaitzidis D, Gilmore T D (2005). Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab, 16(2): 46–52

    Article  PubMed  CAS  Google Scholar 

  • Kaneko M, Niinuma Y, Nomura Y (2003). Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull, 26(7): 931–935

    Article  PubMed  CAS  Google Scholar 

  • Kennedy A, Martinez K, Chuang C C, LaPoint K, McIntosh M (2008). Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. J Nutr, 139(1): 1–4

    Article  PubMed  Google Scholar 

  • Kim S, Jin Y, Choi Y, Park T (2011). Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem Pharmacol, 81(11): 1343–1351

    Article  PubMed  CAS  Google Scholar 

  • Kleinridders A, Schenten D, Könner A C, Belgardt B F, Mauer J, Okamura T, Wunderlich F T, Medzhitov R, Brüning J C (2009). MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab, 10(4): 249–259

    Article  PubMed  CAS  Google Scholar 

  • Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T, van der Burg B, Gustafsson J A (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 139(10): 4252–4263

    Article  PubMed  CAS  Google Scholar 

  • Lehrke M, Lazar M A (2004). Inflamed about obesity. Nat Med, 10(2): 126–127

    Article  PubMed  CAS  Google Scholar 

  • Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra D E, Tsukumo D M, Anhe G, Amaral M E, Takahashi H K, Curi R, Oliveira H C, Carvalheira J B, Bordin S, Saad M J, Velloso L A (2009). Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci, 29(2): 359–370

    Article  PubMed  CAS  Google Scholar 

  • Morgan K, Obici S, Rossetti L (2004). Hypothalamic responses to longchain fatty acids are nutritionally regulated. J Biol Chem, 279(30): 31139–31148

    Article  PubMed  CAS  Google Scholar 

  • Oh-I S, Thaler J P, Ogimoto K, Wisse B E, Morton G J, Schwartz M W (2010). Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding. Am J Physiol Endocrinol Metab, 299(1): E47–E53

    Article  PubMed  CAS  Google Scholar 

  • Park H J, Della-Fera M A, Hausman D B, Rayalam S, Ambati S, Baile C A (2009). Genistein inhibits differentiation of primary human adipocytes. J Nutr Biochem, 20(2): 140–148

    Article  PubMed  CAS  Google Scholar 

  • Park Y J, Jang YM, Kwon Y H (2009). Isoflavones prevent endoplasmic reticulum stress-mediated neuronal degeneration by inhibiting tau hyperphosphorylation in SH-SY5Y cells. J Med Food, 12(3): 528–535

    Article  PubMed  CAS  Google Scholar 

  • Poggi M, Engel D, et al (2011). “CD40L Deficiency Ameliorates Adipose Tissue Inflammation and Metabolic Manifestations of Obesity in Mice.” Arterioscler Thromb Vasc Biol

  • Posey K A, Clegg D J, Printz R L, Byun J, Morton G J, Vivekanandan-Giri A, Pennathur S, Baskin D G, Heinecke J W, Woods S C, Schwartz M W, Niswender K D (2009). Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab, 296(5): E1003–E1012

    Article  PubMed  CAS  Google Scholar 

  • Priego T, Sánchez J, Picó C, Palou A (2009). Sex-associated differences in the leptin and ghrelin systems related with the induction of hyperphagia under high-fat diet exposure in rats. Horm Behav, 55(1): 33–40

    Article  PubMed  CAS  Google Scholar 

  • Reaven G M (1995). Pathophysiology of insulin resistance in human disease. Physiol Rev, 75(3): 473–486

    PubMed  CAS  Google Scholar 

  • Rocha M, Bing C, Williams G, Puerta M (2004). Physiologic estradiol levels enhance hypothalamic expression of the long form of the leptin receptor in intact rats. J Nutr Biochem, 15(6): 328–334

    Article  PubMed  CAS  Google Scholar 

  • Rui L, Yuan M, Frantz D, Shoelson S, White M F (2002). SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem, 277(44): 42394–42398

    Article  PubMed  CAS  Google Scholar 

  • Schwartz MW, Sipols A J, Marks J L, Sanacora G, White J D, Scheurink A, Kahn S E, Baskin D G, Woods S C, Figlewicz D P, et al (1992). Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology, 130(6): 3608–3616

    Article  PubMed  CAS  Google Scholar 

  • Shi H, Clegg D J (2009). Sex differences in the regulation of body weight. Physiol Behav, 97(2): 199–204

    Article  PubMed  CAS  Google Scholar 

  • Stein B, Yang M X (1995). Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol, 15(9): 4971–4979

    PubMed  CAS  Google Scholar 

  • Stice J P, Knowlton A A (2008). Estrogen, NFkappaB, and the heat shock response. Mol Med, 14(7–8): 17–27

    Google Scholar 

  • Straub R H (2007). The complex role of estrogens in inflammation. Endocr Rev, 28(5): 521–574

    Article  PubMed  CAS  Google Scholar 

  • Suganami T, Nishida J, Ogawa Y (2005). A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol, 25(10): 2062–2068

    Article  PubMed  CAS  Google Scholar 

  • Tsukumo D M, Carvalho-Filho M A, Carvalheira J B, Prada P O, Hirabara S M, Schenka A A, Araújo E P, Vassallo J, Curi R, Velloso L A, Saad MJ (2007). Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes, 56(8): 1986–1998

    Article  PubMed  CAS  Google Scholar 

  • Ueki K, Kondo T, Kahn C R (2004). Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol, 24(12): 5434–5446

    Article  PubMed  CAS  Google Scholar 

  • Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C, Krust A, Dupont S, Ciana P, Chambon P, Maggi A (2003). Estrogen receptor-mediates the brain antiinflammatory activity of estradiol. Proc Natl Acad Sci USA, 100(16): 9614–9619

    Article  PubMed  CAS  Google Scholar 

  • Vegeto E, Belcredito S, Ghisletti S, Meda C, Etteri S, Maggi A (2006). The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology, 147(5): 2263–2272

    Article  PubMed  CAS  Google Scholar 

  • Vegeto E, Bonincontro C, Pollio G, Sala A, Viappiani S, Nardi F, Brusadelli A, Viviani B, Ciana P, Maggi A (2001). Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J Neurosci, 21(6): 1809–1818

    PubMed  CAS  Google Scholar 

  • Vinchon M, Weill J, Delestret I, Dhellemmes P (2009). Craniopharyngioma and hypothalamic obesity in children. Childs Nerv Syst, 25(3): 347–352

    Article  PubMed  Google Scholar 

  • Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L (2001). Overfeeding rapidly induces leptin and insulin resistance. Diabetes, 50(12): 2786–2791

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Beydoun M A, Liang L, Caballero B, Kumanyika S K (2008). Will all Americans become overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring), 16(10): 2323–2330

    Article  Google Scholar 

  • Wauman J, Tavernier J (2011). Leptin receptor signaling: pathways to leptin resistance. Front Biosci, 17: 2771–2793

    Article  PubMed  Google Scholar 

  • Weisberg S P, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel R L, Ferrante A W Jr (2006). CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest, 116(1): 115–124

    Article  PubMed  CAS  Google Scholar 

  • Wellen K E, Hotamisligil G S (2003). Obesity-induced inflammatory changes in adipose tissue. J Clin Invest, 112(12): 1785–1788

    PubMed  CAS  Google Scholar 

  • Wellen K E, Hotamisligil G S (2005). Inflammation, stress, and diabetes. J Clin Invest, 115(5): 1111–1119

    PubMed  CAS  Google Scholar 

  • Yang L, Hotamisligil G S (2008). Stressing the brain, fattening the body. Cell, 135(1): 20–22

    Article  PubMed  CAS  Google Scholar 

  • York D, Hansen B (1998). Animal Models of Obesity. Handbook of Obesity. G. Bray, C. Bouchard and W. James. New York, Marcel Dekker, Inc.

  • Yu H P, Hsu J C, Hwang T L, Yen C H, Lau Y T (2008). Resveratrol attenuates hepatic injury after trauma-hemorrhage via estrogen receptor-related pathway. Shock, 30(3): 324–328

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell, 135(1): 61–73

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clifton A. Baile.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miller, C.N., Brown, L.M., Rayalam, S. et al. Estrogens, inflammation and obesity: an overview. Front. Biol. 7, 40–47 (2012). https://doi.org/10.1007/s11515-011-1174-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-011-1174-y

Keywords

Navigation