REVIEW

Estrogens, inflammation and obesity: an overview

  • Colette N. MILLER 1 ,
  • Lynda M. BROWN 2 ,
  • Srujana RAYALAM 3 ,
  • Mary Anne DELLA-FERA 3 ,
  • Clifton A. BAILE , 1,3
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  • 1. Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA
  • 2. Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27401, USA
  • 3. Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602, USA

Received date: 25 Jul 2011

Accepted date: 29 Aug 2011

Published date: 01 Feb 2012

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

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.

Cite this article

Colette N. MILLER , Lynda M. BROWN , Srujana RAYALAM , Mary Anne DELLA-FERA , Clifton A. BAILE . Estrogens, inflammation and obesity: an overview[J]. Frontiers in Biology, 2012 , 7(1) : 40 -47 . DOI: 10.1007/s11515-011-1174-y

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.
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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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