She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism.

To study mechanisms by which free fatty acids (FFAs) cause hepatic insulin resistance, we have used euglycemichyperinsulinemic clamping with and without infusion of lipid/heparin (to raise or to lower plasma FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (؉210%), increased activities of two serine/threonine kinases (protein kinase C-␦ and inhibitor of B [IB] kinase-␤), increased activation of the proinflammatory nuclear factor-B (NF-B) pathway (IB kinase-␤, ؉640%; IB-␣, ؊54%; and NF-B, ؉73%), and increased expression of inflammatory cytokines (tumor necrosis factor-␣, ؉1,700% and interleukin-1␤, ؉440%) and plasma levels of monocyte chemoattractant protein-1 (؉220%). We conclude that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis. Diabetes 54: 3458 -3465, 2005 O besity is closely associated with insulin resistance, type 2 diabetes, and the metabolic syndrome (also called the insulin resistance syndrome) (1). Obesity is also associated with increased presence in the circulation of several proinflammatory cytokines and chemokines and because of that has also been considered an inflammatory condition (rev. in 2). Whereas the reason for these associations is not entirely clear, it has been established that free fatty acids (FFAs) are a major link between obesity and insulin resistance/type 2 diabetes. This is based on the following evidence: most obese people have elevated plasma FFA levels, and FFAs cause insulin resistance dose dependently in skeletal muscle and liver (rev in 3). In skeletal muscle, FFAs inhibit insulin-stimulated glucose uptake at the level of glucose transport and/or phosphorylation (4,5) through mechanisms that involve intramyocellular accumulation of diacylglycerol (DAG) and long-chain acyl-CoA, activation of protein kinase C (PKC), and decreased tyrosine phosphorylation of insulin receptor substrate 1/2 (IRS-1/2) (6,7). The mechanisms by which FFAs cause hepatic insulin resistance have been directly addressed by only one study. In that study, Lam et al. (8) have shown that infusion of lipids (which increased plasma FFA levels) resulted in activation of PKC-␦ in rat liver.In the present study, we have used the lipid/heparin infusion to study effects of acutely elevated plasma FFA levels on insulin action in the rat liver. In this model, plasma FFA levels rise about equally in the systemic and the portal circulation. This is similar to the situation in postabsorptive, obese individuals who have ϳ80% of their fat in subcutaneous and intramuscular adipose tissue (releasing FFAs into the peripheral circulation) and ϳ20% of their fat in visceral adipose tissue (releasing FFAs at an increased rate into the portal circulation) (9,10). RESEARCH DESIGN AND METHODSAdult male Sprague-Dawley rats (250 -300 g) were purchased from Charles River Laboratorie...

Leucine is recognized as a nutrient signal; however, the long-term in vivo consequences of leucine signaling and the role of branched-chain amino acid (BCAA) metabolism in this signaling remain unclear. To investigate these questions, we disrupted the BCATm gene, which encodes the enzyme catalyzing the first step in peripheral BCAA metabolism. BCATm(-/-) mice exhibited elevated plasma BCAAs and decreased adiposity and body weight, despite eating more food, along with increased energy expenditure, remarkable improvements in glucose and insulin tolerance, and protection from diet-induced obesity. The increased energy expenditure did not seem to be due to altered locomotor activity, uncoupling proteins, sympathetic activity, or thyroid hormones but was strongly associated with food consumption and an active futile cycle of increased protein degradation and synthesis. These observations suggest that elevated BCAAs and/or loss of BCAA catabolism in peripheral tissues play an important role in regulating insulin sensitivity and energy expenditure.