Disrupted Hypothalamic CRH Neuron Responsiveness Contributes to Diet-induced Obesity

The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed to by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here we show that HFD feeding blunts PVH CRH neuron responses to nutritional challenges as well as stress stimuli and dexamathesone, which normally produce rapid activation and inhibition of these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which show HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models develop rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity, and may contribute to stress-induced obesity.