Fatty acid induced insulin resistance in the brain

The prevalence of obesity, which is considered as a disease, has been increasing uncontrollably over the last two decades. Obesity is a state of disregulated energy homeostasis characterized by hypothalamic resistance to adiposity signals (insulin and leptin). While many factors are involved in the development of obesity, excess dietary fat has been proposed as one of the main causal factors. This causes disrupted energy homeostasis by inducing both leptin and insulin resistance in the central nervous system. Although brain tissue was considered to be insulin independent for a long time, insulin is now recognized to have important functions in the brain in the regulation of feeding behavior, energy expenditure and peripheral metabolism to maintain energy homeostasis. Recently, our lab discovered that insulin has an anorectic effect when it is applied into the central nucleus of the amygdala (CeA), a response that is similar to its effect when it is intracerebroventricularly (icv) administered into the hypothalamus. Our lab also demonstrated that rats fed a high fat diet lost the anorectic response to CeA insulin and became insulin resistant. These data suggested that insulin signaling in the amygdala had an important role in controlling food intake and energy expenditure in similar ways to the hypothalamus. It also suggests that a high fat diet inhibits amygdala insulin signaling in the CeA. Both in vitro cell culture and in vivo animal studies have been used to investigate the effects of dietary fats on insulin signaling in neuronal cells and in the amygdala. Using both hypothalamic GT1-7 cells and primary amygdala cells in culture, the saturated fatty acid palmitic acid was shown to inhibit insulin signaling (Akt phosphorylation). This response appears to be related to the activation of PKC-theta since the inhibitory effect of palmitic acid on Akt phosphorylation was greater in GT1-7 cells transfected with PKC-theta compared to wild type cells and was abolished in GT1-7 cells transfected with PKC-theta siRNA. Further investigations in vivo confirmed that insulin stimulated Akt and mTOR signaling in the CeA of rats and that the insulin stimulation of Akt phosphorylation, but not mTOR phosphorylation, was inhibited in rats fed a high fat diet for 3 days or by infusing palmitic acid into the CeA for 3 days. These experiments also identified that fatty acid and insulin signaling in the CeA differentially affected Akt and mTOR signaling in the hypothalamus and suggest that these neural connections might be important components of the neural pathways through which insulin in the amygdala affects food intake and peripheral metabolism. This research has provided novel insight into the effects of dietary fats on insulin signaling in an area of the brain, the CeA, that is now recognized to have effects on energy balance and peripheral metabolism.