Estrogens, inflammation and obesity: an overview

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.

Keywords

inflammation / obesity / sex differences / estrogen / high fat diets / phytoestrogens

References

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

[2] 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

[3] Berthoud H R, Morrison C (2008). The brain, appetite, and obesity. Annu Rev Psychol, 59(1): 55-92

[4] 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

[5] 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 diet-fed mice. Am J Physiol Endocrinol Metab, 295(4): E904-E912

[6] 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

[7] 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

[8] 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

[9] 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

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

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

[12] 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

[13] 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

[14] 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

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

[16] 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

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

[18] 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

[19] 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 agouti-related protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology, 149(7): 3346-3354

[20] 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

[21] 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

[22] 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

[23] Haslam D W, James W P (2005). Obesity. Lancet, 366(9492): 1197-1209

[24] Hetherington R, Ranson S (1940). Hypothalamic lesions and adiposity in the rat. Anat Rec, 78(2): 149-172

[25] 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

[26] 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

[27] Hotamisligil G S (2006). Inflammation and metabolic disorders. Nature, 444(7121): 860-867

[28] 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

[29] Kahn B B, Flier J S (2000). Obesity and insulin resistance. J Clin Invest, 106(4): 473-481

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

[31] 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

[32] 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

[33] 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

[34] 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

[35] 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

[36] Lehrke M, Lazar M A (2004). Inflamed about obesity. Nat Med, 10(2): 126-127

[37] 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

[38] Morgan K, Obici S, Rossetti L (2004). Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem, 279(30): 31139-31148

[39] 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

[40] 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

[41] Park Y J, Jang Y M, 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

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

[43] 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

[44] 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

[45] Reaven G M (1995). Pathophysiology of insulin resistance in human disease. Physiol Rev, 75(3): 473-486

[46] 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

[47] 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

[48] Schwartz M W, 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, (1992). Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology, 130(6): 3608-3616

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

[50] 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

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

[52] Straub R H (2007). The complex role of estrogens in inflammation. Endocr Rev, 28(5): 521-574

[53] 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

[54] 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 M J (2007). Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes, 56(8): 1986-1998

[55] 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

[56] 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

[57] 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

[58] 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

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

[60] 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

[61] 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

[62] Wauman J, Tavernier J (2011). Leptin receptor signaling: pathways to leptin resistance. Front Biosci, 17: 2771-2793

[63] 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

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

[65] Wellen K E, Hotamisligil G S (2005). Inflammation, stress, and diabetes. J Clin Invest, 115(5): 1111-1119

[66] Yang L, Hotamisligil G S (2008). Stressing the brain, fattening the body. Cell, 135(1): 20-22

[67] York D, Hansen B (1998). Animal Models of Obesity. Handbook of Obesity. G. Bray, C. Bouchardand W.James. New York, Marcel Dekker, Inc.

[68] 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

[69] 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

Acknowledgments

This review was written under the financial support of USDA ARS NC06871 and the UNCG Office of Research and Economic Development New Faculty grant.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg