Role of metabolic inflammation in depressive behavior
Obesity and diabetes are significant risk factors for mood disorders. Diabetes doubles the incidence of depression and as many as 1 in 3 people with diabetes has depressed mood at a level that diminishes functioning, glycemic control, adherence to treatment and increases the risk of diabetes complications. Over consumption of energy-dense foods significantly contribute to the development of obesity and type 2 diabetes (T2D). Palatable high-fat foods are rewarding and can provide short-term relief from stress and negative emotional states. On the other hand, we have shown that prolonged intake of a high-fat diet (HFD) leading to obesity in mice promotes depressive-like behavior to implicate excessive caloric intake as an important element tying obesity to depression. The magnitude of depressive-like behavior was positively associated with neuroplastic adaptations including increased brain-derived neurotrophic factor (BDNF) and phospho-CREB in the nucleus accumbens (NAc), a limbic brain region strongly tied to hedonic and motivational deficits found in depression. BDNF and CREB upregulation in the NAc and are implicated in the etiology of depressed mood and are modulated by nuclear factor kappa B (NF?B), a transcription factor that plays a key role in the in the cellular response to stress, cytokine production and neuroplasticity. Our new data show that prolonged intake of a saturated HFD, but not an isocaloric monounsaturated HFD, leading to obesity, hyperglycemia and glucose intolerance elicits depressive-like behavior and neuroinflammatory responses in the NAc that include activation of NF?B.
Several lines of evidence implicate immune responses in the pathophysiology of depression . Situations favorable to prolonged systemic inflammation such as obesity and T2D provide an avenue thorough which neuroinflammatory responses can be propagated and sustained. Indeed, inflammatory responses are evident in hypothalamic nuclei in high-fat fed mice and they contribute to obesity and glucose intolerance in a manner that depends on IKK?/NF?B signaling. Our new results demonstrate that the saturated HFD regimen, besides promoting peripheral metabolic inflammation, triggers neuroinflammation in the NAc including reactive gliosis (brain immune cell microglia activation and astrogliosis), increased expression of IL1? and TNF?, activation of NF?B and leukocyte infiltration. Together, our new findings clearly demonstrate that a saturated HFD leading to obesity, hyperinsulinemia and glucose intolerance elicits metabolic neuroinflammation in brain nuclei strongly implicated in the control of mood and motivation. Our global objective is to identify the neural processes by which high-fat feeding, weight gain and T2D lead to depressive-like behavior. We hypothesize that saturated high-fat feeding and the development of hyperglycemia progressively leads to metabolic neuroinflammation in the NAc to elicit cell injury, neuroplastic changes (increased BDNF and CREB) and depressive behavior in an IKK?/NF?B-dependent manner. The proposed project will test two specific hypotheses:
