The increasing prevalence of obesity and type 2 diabetes in developed and developing countries over the past few decades is in large part owing to lifestyle changes that promote excessive energy intake and reduced energy expenditure. Energy balance and metabolic homeostasis are tightly controlled by interconnected nutritional, hormonal, and neural regulatory systems, which are responsible for finely tuned responses in feeding behavior and metabolic processes. One consequence of nutrient overload and positive net energy balance is the development of resistance to the normal action of insulin. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissues, resulting from abnormalities of fat metabolism (either storage or lipolysis), is both a consequence of insulin resistance and an aggravating factor, participating in and amplifying many of the fundamental metabolic derangements that are characteristic of insulin resistance and type 2 diabetes. Adverse metabolic consequences of increased FFA flux and cytosolic lipid accumulation include, but are not limited to, dyslipidemia, impaired hepatic and muscle metabolism, decreased insulin clearance, and impaired pancreatic ^-cell function. In addition, there is increasing appreciation that obesity and insulin resistance are chronic inflammatory states, with inflammatory mediators aggravating obesity-associated insulin resistance. There is growing evidence that FFAs activate the NFkB inflammatory pathway through action on the IKK^ kinase, thereby amplifying a pro-inflammatory response, which is tightly linked to impaired insulin signalling. Weight loss through reduction of caloric intake and increase in physical activity, among other effects reduces plasma FFAs, and cytosolic triglycerides (TGs) in extra-adipose

From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M. N. Feinglos and M. A. Bethel © Humana Press, Totowa, NJ

tissue, and can prevent the development of, and ameliorate the adverse manifestations of, diabetes. Future therapies that specifically modulate fat metabolism by inhibiting adipose tissue lipolysis or by activating fatty acid oxidation, thereby reducing plasma FFA concentrations and tissue lipid accumulation, may result in improvement in some or all of the above metabolic derangements, or prevent progression from insulin resistance to type 2 diabetes. This chapter will expand on these concepts by highlighting the mechanisms underlying dysregulation of fatty acid metabolism in insulin resistant states, the causative role of fatty acid metabolites in initiating and aggravating these metabolic disorders, and possibilities regarding fat metabolism as a therapeutic target.

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