Sex hormone imbalances and adipose tissue dysfunction impacting on metabolic syndrome; a paradigm for the discovery of novel adipokines

Hui Zhang 1  and M. Ram Sairam 1
  • 1 Molecular Endocrinology Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal H2W 1R7, Quebec, Canada
Hui Zhang and M. Ram Sairam

Abstract

Sex hormone imbalance is causally related with visceral adipose tissue (AT) dysfunction and visceral obesity – an etiological component of metabolic syndrome (MetS), associated with high risk of both cardiovascular disease (CVD) and type 2 diabetes. In general, premenopausal women appear to be protected from CVD and the dramatic decline in sex steroid hormone occurring during menopausal transitions or other sex-related disorders influence the regional distribution, function, and metabolism of AT and increase the risk of CVD. Visceral AT dysfunction, manifesting as abnormality of fatty acid metabolism, increased oxidative stress, endothelial dysfunction, and excessive production of adipokines have been proposed in the pathogenesis of MetS. However, direct evidence of molecular mechanisms of depot-specific AT alterations, and dysfunction causally related to MetS is limited in studies on postmenopausal women due to difficulty in collecting discrete AT specimens at different ages and repeated sampling from different fat depots. This can be overcome using animal models that can mimic the cluster of pathology leading to MetS and help establish the molecular basis of links between loss of gonadal function on various AT depots and their contribution to MetS. Our group used sex hormone imbalance FSH receptor knock out (FORKO) female mice to recapitulate different aspects of the MetS and addressed the mechanism of visceral obesity related to MetS and discover two novel sex steroid hormone-regulated deep mesenteric estrogen-dependent adipose (MEDAs) genes. Taken together, such recent studies raise hopes for pharmacologic intervention strategies targeting sex steroid hormone signaling in AT to provide protection against AT dysfunction.

  • 1.

    Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9.

  • 2.

    Nikolopoulou A, Kadoglou NP. Obesity and metabolic syndrome as related to cardiovascular disease. Expert Rev Cardiovas Ther 2012;10:933–9.

  • 3.

    Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 2004;27:2444–9.

  • 4.

    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002;287:356–9.

  • 5.

    Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide populations. Endocrinol Metab Clin North Am 2004;33:351–75.

  • 6.

    Scaglione R, Di Chiara T, Cariello T, Licata G. Visceral obesity and metabolic syndrome: two faces of the same medal? Intern Emerg Med 2010;5:111–9.

  • 7.

    Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – a new worldwide definition. Lancet 2005;366:1059–62.

  • 8.

    Grundy SM, Hansen B, Smith SC, Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on scientific issues related to management. Circulation 2004;109:551–6.

  • 9.

    Ness-Abramof R, Apovian CM. Waist circumference measurement in clinical practice. Nutr Clin Pract 2008;23: 397–404.

  • 10.

    Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP T, Loria CM, Smith SC. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–5.

  • 11.

    Sammartino A, Cirillo D, Mandato VD, Di Carlo C, Nappi C. Osteoporosis and cardiovascular disease: benefit-risk of hormone replacement therapy. J Endocrinol Invest 2005;28: 80–84.

  • 12.

    Larsson B, Bengtsson C, Bjorntorp P, Lapidus L, Sjostrom L, Svardsudd K, Tibblin G, Wedel H, Welin L, Wilhelmsen L. Is abdominal body fat distribution a major explanation for the sex difference in the incidence of myocardial infarction? The study of men born in 1913 and the study of women, Goteborg, Sweden. Am J Epidemiol 1992;135:266–73.

  • 13.

    Gambacciani M, Ciaponi M, Cappagli B, Piaggesi L, De Simone L, Orlandi R, Genazzani AR. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 1997;82:414–7.

  • 14.

    Orio F, Jr., Palomba S, Spinelli L, Cascella T, Tauchmanova L, Zullo F, Lombardi G, Colao A. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 2004;89:3696–701.

  • 15.

    Munoz J, Derstine A, Gower BA. Fat distribution and insulin sensitivity in postmenopausal women: influence of hormone replacement. Obes Res 2002;10:424–31.

  • 16.

    Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D. Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 1997;7:390–406.

  • 17.

    Szmuilowicz ED, Stuenkel CA, Seely EW. Influence of menopause on diabetes and diabetes risk. Nat Rev Endocrinol 2009;5:553–8.

  • 18.

    Rosano GM, Vitale C, Fini M. Cardiovascular aspects of menopausal hormone replacement therapy. Climacteric 2009;12(Suppl 1):41–6.

  • 19.

    Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. J Am Med Assoc 2007;297:1465–77.

  • 20.

    Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26:833–76.

  • 21.

    Wespes E, Schulman CC. Male andropause: myth, reality, and treatment. Int J Impot Res 2002;14(Suppl 1):S93–8.

  • 22.

    Corrales JJ, Burgo RM, Garca-Berrocal B, Almeida M, Alberca I, Gonzalez-Buitrago JM, Orfao A, Miralles JM. Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control. Metabolism 2004;53:666–72.

  • 23.

    Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes 2008;32:1431–7.

  • 24.

    Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008;93 (11 Suppl 1):S9–30.

  • 25.

    Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006;84:289–98.

  • 26.

    Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011;377:557–67.

  • 27.

    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.

  • 28.

    Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404–11.

  • 29.

    Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004;30:13–9.

  • 30.

    Inadera H. The usefulness of circulating adipokine levels for the assessment of obesity-related health problems. Int J Med Sci 2008;5:248–62.

  • 31.

    Bjorntorp P. “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis (Dallas, Tex) 1990;10:493–6.

  • 32.

    Schaffler A, Scholmerich J, Buchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue – emerging role in intestinal and mesenteric diseases. Nat Clin Pract Gastroenterol Hepatol 2005;2:103–11.

  • 33.

    Catalano KJ, Stefanovski D, Bergman RN. Critical role of the mesenteric depot versus other intra-abdominal adipose depots in the development of insulin resistance in young rats. Diabetes 2010;59:1416–23.

  • 34.

    Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E, Shai I, Kloting N, Stumvoll M, Bashan N, Rudich A. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007;92:2240–7.

  • 35.

    Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 2003;46: 1297–312.

  • 36.

    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science (New York, NY) 1993;259:87–91.

  • 37.

    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.

  • 38.

    Szymczak J, Milewicz A, Thijssen JH, Blankenstein MA, Daroszewski J. Concentration of sex steroids in adipose tissue after menopause. Steroids 1998;63:319–21.

  • 39.

    Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev 2004;5:197–216.

  • 40.

    Ferrara CM, Lynch NA, Nicklas BJ, Ryan AS, Berman DM. Differences in adipose tissue metabolism between postmenopausal and perimenopausal women. J Clin Endocrinol Metab 2002;87:4166–70.

  • 41.

    Tchernof A, Després J-P. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013;93:359–404.

  • 42.

    Tchernof A, Desmeules A, Richard C, Laberge P, Daris M, Mailloux J, Rhéaume C, Dupont P. Ovarian hormone status and abdominal visceral adipose tissue metabolism. J Clin Endocrinol Metab 2004;89:3425–30.

  • 43.

    Bluher M. Importance of estrogen receptors in adipose tissue function. Mol Metab 2013;2:130–2.

  • 44.

    Cooke PS, Heine PA, Taylor JA, Lubahn DB. The role of estrogen and estrogen receptor-alpha in male adipose tissue. Mol Cell Endocrinol 2001;178:147–54.

  • 45.

    Zhang H, Chen X, Aravindakshan J, Sairam MR. Changes in adiponectin and inflammatory genes in response to hormonal imbalances in female mice and exacerbation of depot selective visceral adiposity by high-fat diet: implications for insulin resistance. Endocrinology 2007;148:5667–79.

  • 46.

    Sairam MR, Wang M, Danilovich N, Javeshghani D, Maysinger D. Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances. Obesity 2006;14:1142–54.

  • 47.

    Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 2000;97:12729–34.

  • 48.

    Misso ML, Murata Y, Boon WC, Jones ME, Britt KL, Simpson ER. Cellular and molecular characterization of the adipose phenotype of the aromatase-deficient mouse. Endocrinology 2003;144:1474–80.

  • 49.

    Zhang H, Chen X, Sairam MR. Novel genes of visceral adiposity: identification of mouse and human mesenteric estrogen-dependent adipose (MEDA)-4 gene and its adipogenic function. Endocrinology 2012;153:2665–76.

  • 50.

    Zhang H, Chen X, Sairam MR. Novel hormone-regulated genes in visceral adipose tissue: cloning and identification of proinflammatory cytokine-like mouse and human MEDA-7: implications for obesity, insulin resistance and the metabolic syndrome. Diabetologia 2011;54:2368–80.

  • 51.

    Davis KE, Neinast MD, Sun K, Skiles MS, Bills JD, Zehr JA, Zeve D, Hahner LD, Cox DW, Gent LM, Xu Y, Wang ZV, Khan SA, Clegg DJ. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol Metab 2013;2:227–42.

  • 52.

    Shimizu Y, Meunier L, Hendershot LM. pERp1 is significantly up-regulated during plasma cell differentiation and contributes to the oxidative folding of immunoglobulin. Proc Natl Acad Sci USA 2009;106:17013–18.

  • 53.

    van Anken E, Pena F, Hafkemeijer N, Christis C, Romijn EP, Grauschopf U, Oorschot VMJ, Pertel T, Engels S, Ora A, Lástun V, Glockshuber R, Klumperman J, Heck AJR, Luban J, Braakman I. Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1. Proc Natl Acad Sci 2009;106:17019–24.

  • 54.

    Flach H, Rosenbaum M, Duchniewicz M, Kim S, Zhang SL, Cahalan MD, Mittler G, Grosschedl R. Mzb1 protein regulates calcium homeostasis, antibody secretion, and integrin activation in innate-like B cells. Immunity 2010;33:723–35.

Purchase article
Get instant unlimited access to the article.
$42.00
Log in
Already have access? Please log in.


or
Log in with your institution

Journal + Issues

Hormone Molecular Biology and Clinical Investigation is dedicated to the provision of data on molecular aspects of hormones in physiology and pathophysiology. The journal covers the treatment of diseases, such as endocrine cancers, renal and lymphoid carcinoma, hypertension, cardiovascular systems, osteoporosis, hormone deficiency in menopause and andropause, obesity, diabetes, brain and related diseases.

Search