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Disrupted hypothalamic CRH neuron responsiveness contributes to diet-induced obesity.

ABSTRACT: The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed 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 found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which showed HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models developed rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rhythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity and may also contribute to stress-induced obesity.

SUBMITTER: Zhu C

PROVIDER: S-EPMC7332802 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Disrupted Hypothalamic CRH Neuron Responsiveness Contributes to Diet-induced Obesity

Project description: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.

| S-SCDT-EMBOR-2019-49210V1 | biostudies-other

Hypothalamic neural projections are permanently disrupted in diet-induced obese rats.

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Stress experience and hormone feedback tune distinct components of hypothalamic CRH neuron activity.

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Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity.

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Project description:Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of ?-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of ?-endorphin levels, is the earliest hypothalamic defect leading to obesity.

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