Introductory Review Cellscience Reviews Vol.2 No.4 ISSN 1742-8130

SH2-B Regulation of Leptin Sensitivity, Energy Balance and Body Weight

Abstract

Energy balance and body weight are largely controlled by a homeostatic regulatory system. Leptin, a polypeptide hormone secreted by adipose tissue, conveys information about energy storage and availability to the hypothalamus. The hypothalamus is the key area that senses and integrates various neuronal, hormonal and nutrient-related signals. Leptin binds to its receptor LEPRb, thus activating multiple signaling pathways. LEPRb is highly expressed in two groups of neurons in the arcuate nucleus in the hypothalamus, which coexpress either orexigenic NPY/AgRP or anorexigenic POMC/CART. Leptin inhibits NPY/AgRP neurons and stimulates POMC/CART neurons, resulting in both a decrease in energy intake and an increase in energy expenditure. Leptin resistance is a hallmark and key determinant of obesity. Leptin sensitivity is modulated by a balance between negative regulators SOCS3 and PTP1B and a positive regulator SH2-B. SH2-B binds directly to JAK2, a cytoplasmic tyrosine kinase that binds to LEPRb and mediates leptin signaling. SH2-B enhances leptin signaling by both promoting JAK2 activation and recruiting downstream signaling molecules.

Introduction

Body weight is determined by a balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, excess energy is stored as triglyceride in adipose tissue, leading to excess weight gain or obesity. Body weight is normally maintained within a narrow range, suggesting that body weight and energy metabolism are controlled by a biological homeostatic system. The hypothalamus is the key area in the central nervous system (CNS) that senses and integrates various neuronal, hormonal and nutrient-related signals. Adipose tissue produces and secrets hormones (adiposity signals), which convey information about peripheral energy availability and storage to the hypothalamus. Leptin is one of the most important adipose hormones that control energy balance and body weight. Genetic deficiency in either leptin or its receptor results in morbid obesity in both rodents and humans (1-6).

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