Role of the Adipocyte in Type 2 Diabetes

Abstract

Obesity is a major risk factor for several pathophysiological disorders including type 2 diabetes and cardiovascular disease. Obese individuals, particularly those with excess adipose tissue around their major organs, lose the ability to respond to insulin and eventually develop hyperinsulinemia and hyperlipidemia. If left untreated, these individuals are at risk for developing type 2 diabetes and cardiovascular disease. Investigations during the last few years have focused on the adipocyte as a potential link between obesity and insulin resistance. The conclusions drawn from this research implicate the adipocyte as a central player in the development of insulin resistance, affecting muscle and liver of individuals with excess adipose tissue. In fact, the role of the adipocyte in regulating overall energy balance has been significantly redefined. Specifically, in addition to storing excess energy as triglycerides, adipocytes secrete many biologically active molecules that regulate mechanisms related to energy balance in other metabolically active tissues including the brain, muscle, and liver. These bioactive molecules include hormones and several cytokines, collectively referred to as adipocytokines , which include leptin, tumor necrosis factor α (TNF‐α), adiponectin/ACRP30/adipoQ/apM1, and resistin. Certain adipocytokines have been directly linked to insulin resistance in obese humans as well as in various animal models. An approach to combating type 2 diabetes mellitus, therefore, is to understand the molecular and physiological mechanisms that regulate the formation and function of adipocytes in specific adipose tissue depots. This chapter discusses the role of adipogenic transcription factors in regulating adipogenesis and metabolic homeostasis. Attention is given to the nuclear hormone receptor PPAR‐γ (peroxisome proliferator‐activated receptor γ) which is a master regulator of adipocyte differentiation and the target of the thiazolidinedione family of antidiabetic drugs. In this regard, the mechanism of action of the thiazolidinediones is discussed and other adipocyte proteins are proposed as alternative targets for the development of antidiabetic therapeutics.