Adipokines and the peripheral and neural control of energy balance

Abstract

Adipokines are secreted by adipose tissue and control various physiological systems. Low leptin levels during fasting stimulate feeding, reduce energy expenditure, and modulate neuroendocrine and immune function to conserve energy stores. On the other hand, rising leptin levels in the overfed state prevent weight gain by inhibiting food intake and increasing energy expenditure. These actions are mediated by neuronal circuits in the hypothalamus and brainstem. Leptin also controls glucose and lipid metabolism by targeting enzymes such as AMP-activated protein kinase and stearoyl-coenzyme A desaturase-1 in liver and muscle. Likewise, adiponectin and resistin control energy balance and insulin sensitivity via central and peripheral targets. As highlighted in this review, there are distinct as well as common signaling pathways for adipokines. Understanding adipokine signaling in the brain and other organs will provide insights into the pathogenesis and treatment of obesity, diabetes and various metabolic disorders.

Figure 1

Intracellular Signaling Pathways Regulated by LRb Binding of leptin to the extracellular domain of LRb activates JAK2 tyrosine kinase leading to autophosphorylation of tyrosine residues on JAK2 and phosphorylation of Tyr ⁹⁸⁵, Tyr¹⁰⁷⁷, and Tyr¹¹³⁸ on LRb. Phosphorylation of Tyr¹¹³⁸ mediates the activation and nuclear translocation of STAT3, which induces the transcription neuropeptides in the hypothalamus as well as SOCS3, which terminates leptin signaling. Tyr⁹⁸⁵ also promotes interaction of SOCS3 with LRb-JAK2, thereby attenuating leptin signaling. Tyr¹⁰⁷⁷ plays a dominant role in the transcriptional activation of STAT5, and this action is inhibited by Tyr¹¹³⁸-STAT3. SHP2, Src homology 2-containing tyrosine phosphatase-2.

Figure 2

Leptin Signaling in the Hypothalamus Leptin binds to LRb on NPY/AGRP and POMC/cocaine- and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus, leading to inhibition of feeding, and stimulation of thermogenesis, fatty acid oxidation, and enhancement of peripheral insulin sensitivity. Leptin-sensitive neurons in the arcuate nucleus project to the paraventricular nucleus to increase CRH and TRH, and lateral hypothalamic area to suppress melanin-concentrating hormone (MCH) and orexins (ORX). Leptin also inhibits AMPK phosphorylation.

Figure 3

Adiponectin and Resistin Signaling in the Liver High adiponectin levels in lean individuals bind to AdipoR1 and -R2 in the liver, leading to phosphorylation and activation of AMPK and increased PPARα activity. Adiponectin stimulates fatty acid oxidation, prevents steatosis, enhances insulin signaling, and suppresses hepatic glucose production. Resistin is increased in obesity, inhibits AMPK activity, increases SOCS3, and induces insulin resistance.