Kershaw and Flier • Adipose Tissue as an Endocrine Organ
TABLE 1. Examples of adipocyte-derived proteins with endocrine functions Cytokines and cytokinerelated proteins Other immune-related proteins Proteins involved in the fibrinolytic system Complement and complement-related proteins Lipids and proteins for lipid metabolism or transport
Enzymes involved in steroid metabolism Proteins of the RAS Other proteins
Leptin TNF␣ IL-6 MCP-1 PAI-1 Tissue factor Adipsin (complement factor D) Complement factor B ASP Adiponectin Lipoprotein lipase (LPL) Cholesterol ester transfer protein (CETP) Apolipoprotein E NEFAs Cytochrome P450dependent aromatase 17HSD 11HSD1 AGT Resistin
TABLE 2. Examples of receptors expressed in adipose tissue Receptors for traditional endocrine hormones
Nuclear hormone receptors
Cytokine receptors Catecholamine receptors
Insulin receptor Glucagon receptor GH receptor TSH receptor Gastrin/CCK-B receptor Glucagon like peptide-1 receptor Angiotensin II receptors type 1 and 2 Glucocorticoid receptor Vitamin D receptor Thyroid hormone receptor Androgen receptor Estrogen receptor Progesterone receptor Leptin receptor IL-6 receptor TNF␣ receptor 1, 2, 3 receptors ␣1, ␣2 receptors
mology to cytokines. Adipocytes secrete leptin in direct proportion to adipose tissue mass as well as nutritional status, and this secretion is greater from sc relative to visceral adipose tissue (9, 14). Leptin expression and secretion are also regulated by a variety of other factors. For example, leptin is increased by insulin, glucocorticoids, TNF␣, estrogens, and CCAAT/enhancer-binding protein-␣ and decreased by 3adrenergic activity, androgens, free fatty acids, GH, and peroxisome proliferator-activated receptor-␥ agonists (15). Leptin receptors are members of the cytokine receptor class I superfamily and are expressed in both the CNS and periphery (16). Although several splice variants of the leptin receptor have been identified, the long form mediates the majority of leptin’s myriad effects (16). The effects of leptin on energy homeostasis are well documented (17). Many of these effects, particularly on energy
J Clin Endocrinol Metab, June 2004, 89(6):2548 –2556 2549
intake and expenditure, are mediated via hypothalamic pathways, whereas other effects are mediated via direct action on peripheral tissues including muscle and pancreatic -cells (16). Although initially viewed as an antiobesity hormone, leptin’s primary role is to serve as a metabolic signal of energy sufficiency rather than excess (18). Leptin levels rapidly decline with caloric restriction and weight loss. This decline is associated with adaptive physiological responses to starvation including increased appetite and decreased energy expenditure. These same responses are observed in leptin-deficient mice and humans, despite massive obesity. Furthermore, these responses are readily normalized by lowdose leptin replacement. In contrast, common forms of obesity are characterized by elevated circulating leptin. Neither endogenously high leptin levels nor treatment with exogenous leptin is effective in ameliorating this obesity, consistent with a state of leptin resistance (16, 19). The mechanism for leptin resistance is unknown but may result from defects in leptin signaling or transport across the blood-brain barrier (16, 19). Clearly, the most sensitive portion of the leptin dose-response curve resides in the physiological range between the low levels induced by food restriction and the rising levels induced by refeeding and not in the supraphysiological range associated with obesity. This role of leptin as an indicator of energy sufficiency makes sense from an evolutionary perspective but provides no consolation in our current environment of energy abundance. In addition to its effects on energy homeostasis, leptin regulates neuroendocrine function and traditional endocrine systems. Leptin deficiency in Lepob/Lepob mice is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and suppression of the hypothalamic-pituitary-thyroid and -gonadal axes. Leptin decreases hypercortisolemia in Lepob/Lepob mice, inhibits stress-induced secretion of hypothalamic CRH in mice, and inhibits cortisol secretion from rodent and human adrenocortical cells in vitro. The role of leptin in HPA activity in humans in vivo remains unclear. Leptin also normalizes suppressed thyroid hormone levels in leptin-deficient mice and humans, in part via stimulation of TRH expression and secretion from hypothalamic TRH neurons (16, 20). Leptin accelerates puberty in normal mice and restores normal gonadotropin secretion and reproductive function in leptin-deficient mice and humans (21). Leptin replacement during fasting prevents starvation-induced changes in the hypothalamic-pituitary-gonadal and -thyroid axes in healthy men (22). Leptin also has direct effects via peripheral leptin receptors in the ovary, testis, prostate, and placenta (15). Several other important endocrine effects of leptin include regulation of immune function, hematopoiesis, angiogenesis, and bone development. Leptin normalizes the suppressed immune function associated with malnutrition and leptin deficiency (23). Leptin also promotes proliferation and differentiation of hematopoietic cells, alters cytokine production by immune cells, stimulates endothelial cell growth and angiogenesis, and accelerates wound healing (15). An important role for leptin in bone development is supported by the observation that leptin-deficient Lepob/ Lepob mice have increased bone mass, despite hypercortisolemia and hypogonadism (24). Chemical lesions of specific
Downloaded from jcem.endojournals.org on August 8, 2005