We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. Inhibition of this activity by treating the cells with a MEK1-specific inhibitor (U0126 or PD98059) prior to the induction of differentiation significantly attenuated the expression of peroxisome proliferator-activated receptor (PPAR) ␥, CCAAT/enhancer-binding protein (C/EBP) ␣, perilipin, and adipocyte-specific fatty acid-binding protein (aP2). Treating the preadipocytes with troglitazone, a potent PPAR␥ ligand, could circumvent the inhibition of adipogenic gene expression by U0126. Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors. Consequently, preadipocytes treated with U0126 in the presence of fibroblast growth factor-2 (FGF-2) express normal post-induction levels of MEK activity, and, in so doing, are capable of undergoing adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBP␣ minimal promoter during the early phase of the differentiation process. Our results suggest that activation of the MEK/ ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBP␣ and PPAR␥ expression.

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.

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