Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk

Abstract

Metabolism research has made tremendous progress over the last several decades in establishing the adipocyte as a central rheostat in the regulation of systemic nutrient and energy homeostasis. Operating at multiple levels of control, the adipocyte communicates with organ systems to adjust gene expression, glucoregulatory hormone exocytosis, enzymatic reactions, and nutrient flux to equilibrate the metabolic demands of a positive or negative energy balance. The identification of these mechanisms has great potential to identify novel targets for the treatment of diabetes and related metabolic disorders. Herein, we review the central role of the adipocyte in the maintenance of metabolic homeostasis, highlighting three critical mediators: adiponectin, leptin, and fatty acids.

Keywords: adipokines; adiponectin; leptin; lipid signaling.

Figure 1. Autocrine signaling in the adipocyte

Adiponectin, which increases as fat mass decreases, acts locally on the adipocyte to increase GLUT4- mediated glucose uptake, while enhancing adipogenesis and adipocyte lipid storage. Fasting and leptin independently increase adipose tissue lipolysis, while fasting decreases leptin secretion. The predominant lipolytic action of leptin may be mediated through the peripheral nervous system. A rise in some fatty acids (see text for details) can increase adipocyte GLUT4-mediated glucose uptake.

Figure 2. Adipocyte/liver crosstalk to maintain systemic lipid and glucose homeostasis

Both Leptin and Adiponectin decrease hepatic lipogenesis and increase β-oxidation through activation of AMP protein kinase. Phospo-AMPK inhibits lipogenesis by 1) suppressing SREBP1c expression, and 2) by phosphorylating acetyl CoA carboxylase-1 (ACC-1), the rate-limiting enzyme of de novo lipogenesis. This decrease in ACC-1 activity, limits malonyl CoA production, relieving the inhibition of carnitine palmitoyl transferase-1 (CPT-1) activity and enhancing fatty acid transport into the mitochondria to undergo β-oxidation. Adiponectin lowers hepatic ceramide accumulation, independent of AMPK activity, by enhancing ceramidase activity in the liver. FGF21 stimulates adiponectin secretion. Adiponectin also inhibits hepatic gluconeogenesis, independent of AMPK, decreasing glucose output and improving glycemia. Consequently, enhanced hepatic insulin sensitivity feeds back to the adipocyte to promote adipose tissue insulin sensitivity, resulting in enhanced systemic lipid and glucose homeostasis (see text for details).

Figure 3. A working model of adipocyte/islet communication

Leptin inhibits insulin and glucagon secretion from β- and α-cells, respectively. Whether this is a direct action of leptin or centrally mediated has not been entirely elucidated. The effects of adiponectin on β -cell insulin secretion may depend on circulating glucose concentration, with adiponectin inhibiting insulin secretion at low glucose concentrations and stimulating insulin secretion at high glucose concentrations. Fatty acids enhance glucose stimulated insulin secretion at high glucose conditions. Under fasting conditions, fatty acids may increase glucagon secretion indirectly by limiting somatostatin’s inhibitory effect on α-cell exocytosis and fasting-induced decreases in leptin secretion may act to relieve leptin’s inhibitory effect on glucagon secretion under low blood glucose concentrations.