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Adipose Tissue As an Endocrine Organ

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Adipose Tissue As an Endocrine Organ 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(6):2548–2556 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0395 Adipose Tissue as an Endocrine Organ ERIN E. KERSHAW AND JEFFREY S. FLIER Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215 Adipose tissue is a complex, essential, and highly active met- the renin-angiotensin system, and resistin. Adipose tissue is abolic and endocrine organ. Besides adipocytes, adipose tis- also a major site for metabolism of sex steroids and glucocor- Downloaded from https://academic.oup.com/jcem/article-abstract/89/6/2548/2870285 by guest on 09 April 2020 sue contains connective tissue matrix, nerve tissue, stromo- ticoids. The important endocrine function of adipose tissue is vascular cells, and immune cells. Together these components emphasized by the adverse metabolic consequences of both function as an integrated unit. Adipose tissue not only re- adipose tissue excess and deficiency. A better understanding sponds to afferent signals from traditional hormone systems of the endocrine function of adipose tissue will likely lead to and the central nervous system but also expresses and se- more rational therapy for these increasingly prevalent disor- cretes factors with important endocrine functions. These fac- ders. This review presents an overview of the endocrine func- tors include leptin, other cytokines, adiponectin, complement tions of adipose tissue. (J Clin Endocrinol Metab 89: 2548–2556, components, plasminogen activator inhibitor-1, proteins of 2004) HE TRADITIONAL VIEW of adipose tissue as a passive states (4). The prevalence of obesity and these associated T reservoir for energy storage is no longer valid. As early morbidities, known as the metabolic syndrome, has reached as 1987, adipose tissue was identified as a major site for epidemic proportions (4). Interestingly, adipose tissue defi- metabolism of sex steroids (1) and production of adipsin, an ciency or lipodystrophy is also associated with features of the endocrine factor that is markedly down-regulated in rodent metabolic syndrome in both humans and rodents (5). Fur- obesity (2). The subsequent identification and characteriza- thermore, the prevalence of lipodystrophy in humans is in- tion of leptin in 1994 firmly established adipose tissue as an creasing with the use of highly active antiretroviral therapy endocrine organ (3). Adipose tissue is now known to express for HIV (5). Thus, both excess and deficiency of adipose and secrete a variety of bioactive peptides, known as adi- tissue have harmful metabolic consequences and represent pokines, which act at both the local (autocrine/paracrine) significant medical and socioeconomic burdens in the world and systemic (endocrine) level (Table 1). In addition to these today. efferent signals, adipose tissue expresses numerous recep- It is now clear that adipose tissue is a complex and highly tors that allow it to respond to afferent signals from tradi- active metabolic and endocrine organ (6, 7). Besides adipo- tional hormone systems as well as the central nervous system cytes, adipose tissue contains connective tissue matrix, nerve (CNS) (Table 2). Thus, besides the biological repertoire nec- tissue, stromovascular cells, and immune cells (8). Although essary for storing and releasing energy, adipose tissue con- adipocytes express and secrete several endocrine hormones tains the metabolic machinery to permit communication with such as leptin and adiponectin, many secreted proteins are distant organs including the CNS. Through this interactive derived from the nonadipocyte fraction of adipose tissue (9). network, adipose tissue is integrally involved in coordinat- Regardless, these components function as an integrated unit, ing a variety of biological processes including energy me- making adipose tissue a true endocrine organ (8). Here we tabolism, neuroendocrine function, and immune function. present an overview of the endocrine functions of adipose The important endocrine function of adipose tissue is em- tissue. These functions fall into two broad categories: 1) se- phasized by the adverse metabolic consequences of both creted proteins that have metabolic effects on distant cells or adipose tissue excess and deficiency. Adipose tissue excess tissues, and 2) enzymes involved in the metabolism of steroid or obesity, particularly in the visceral compartment, is as- hormones. sociated with insulin resistance, hyperglycemia, dyslipide- mia, hypertension, and prothrombotic and proinflammatory Adipose Tissue-Secreted Proteins Leptin Abbreviations: ACE, Angiotensin-converting enzyme; AdipoR, adi- Before the identification of leptin, parabiosis studies in ponectin receptor; AGT, angiotensinogen; ASP, acylating simulation protein; AT1, angiotensin II receptor type I; CNS, central nervous sys- mice carrying the recessive mutations, obese (ob) and dia- tem; HPA, hypothalamic-pituitary-adrenal; HSD, hydroxysteroid de- betes (db), predicted the existence of a circulating endocrine hydrogenase; 11␤HSD1, 11␤-hydroxysteroid dehydrogenase type 1; IL- hormone capable of communicating information from the 6R, IL-6 receptor; MCP, monocyte chemotactic protein; NEFA, periphery to the CNS with regard to the sufficiency of energy nonesterified fatty acid; PAI, plasminogen activator inhibitor; RAS, re- stores (10). These predictions were subsequently confirmed nin angiotensin system; SNS, sympathetic nervous system; TZD, ob thiazoladinedione. by the identification of the leptin gene (Lep ) in 1994 (3) and db fa JCEM is published monthly by The Endocrine Society (http://www. its cognate receptor in 1995 and 1996 (Lepr , Lepr ) (11–13). endo-society.org), the foremost professional society serving the en- Leptin (from the Greek leptos, meaning thin) is a 16-kDa docrine community. polypeptide containing 167 amino acids with structural ho- 2548 Kershaw and Flier • Adipose Tissue as an Endocrine Organ J Clin Endocrinol Metab, June 2004, 89(6):2548–2556 2549 TABLE 1. Examples of adipocyte-derived proteins with endocrine intake and expenditure, are mediated via hypothalamic functions pathways, whereas other effects are mediated via direct ac- tion on peripheral tissues including muscle and pancreatic Cytokines and cytokine- Leptin ␤ related proteins TNF␣ -cells (16). Although initially viewed as an antiobesity hor- IL-6 mone, leptin’s primary role is to serve as a metabolic signal Other immune-related MCP-1 of energy sufficiency rather than excess (18). Leptin levels proteins rapidly decline with caloric restriction and weight loss. This Proteins involved in the PAI-1 fibrinolytic system Tissue factor decline is associated with adaptive physiological responses Complement and Adipsin (complement to starvation including increased appetite and decreased en- complement-related factor D) ergy expenditure. These same responses are observed in proteins Complement factor B leptin-deficient mice and humans, despite massive obesity. ASP Adiponectin Furthermore, these responses are readily normalized by low- Downloaded from https://academic.oup.com/jcem/article-abstract/89/6/2548/2870285 by guest on 09 April 2020 Lipids and proteins for lipid Lipoprotein lipase (LPL) dose leptin replacement. In contrast, common forms of obe- metabolism or transport Cholesterol ester transfer sity are characterized by elevated circulating leptin. Neither protein (CETP) endogenously high leptin levels nor treatment with exoge- Apolipoprotein E nous leptin is effective in ameliorating this obesity, consistent NEFAs Enzymes involved in steroid Cytochrome P450- with a state of leptin resistance (16, 19). The mechanism for metabolism dependent aromatase leptin resistance is unknown but may result from defects in 17␤HSD leptin signaling or transport across the blood-brain barrier 11␤HSD1 (16, 19). Clearly, the most sensitive portion of the leptin Proteins of the RAS AGT Other proteins Resistin dose-response curve resides in the physiological range be- tween the low levels induced by food restriction and the rising levels induced by refeeding and not in the supraphysi- TABLE 2. Examples of receptors expressed in adipose tissue ological range associated with obesity. This role of leptin as an indicator of energy sufficiency makes sense from an evo- Receptors for traditional Insulin receptor lutionary perspective but provides no consolation in our endocrine hormones Glucagon receptor current environment of energy abundance. GH receptor TSH receptor In addition to its effects on energy homeostasis, leptin Gastrin/CCK-B receptor regulates neuroendocrine function and traditional endocrine Glucagon like peptide-1 systems. Leptin deficiency in Lepob/Lepob mice is associated receptor with activation of the hypothalamic-pituitary-adrenal (HPA) Angiotensin II receptors axis and suppression of the hypothalamic-pituitary-thyroid type 1 and 2 Nuclear hormone receptors Glucocorticoid receptor and -gonadal axes. Leptin decreases hypercortisolemia in ob ob Vitamin D receptor Lep /Lep mice, inhibits stress-induced secretion of hy- Thyroid hormone pothalamic CRH in mice, and inhibits cortisol secretion from receptor rodent and human adrenocortical cells in vitro. The role of Androgen receptor Estrogen receptor leptin in HPA activity in humans in vivo remains unclear. Progesterone receptor Leptin also normalizes suppressed thyroid hormone levels in Cytokine receptors Leptin receptor leptin-deficient mice and humans, in part via stimulation
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