Abstract
Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.
Highlights
Body weight is regulated by a physiologic system that balances energy intake and expenditure over the long term
We set out to characterize how the regulation of AgRP neurons is modulated by dietinduced obesity and subsequent weight loss
We generated mice equipped for fiber photometry recordings from AgRP neurons (Beutler et al, 2017; Chen et al, 2015) and tested these animals at baseline, after 6 weeks of ad libitum consumption of high-fat diet (HFD) (60% kcal from fat), and again after 4 weeks of ad libitum chow consumption (Figure 1A)
Summary
Body weight is regulated by a physiologic system that balances energy intake and expenditure over the long term. Nothing is known about how diet-induced obesity alters the response of AgRP neurons to sensory cues signaling food availability or their modulation by gastrointestinal nutrients during a meal. These aspects of AgRP neuron regulation cannot be probed using ex vivo methods, such as immunohistochemistry or slice physiology, due to their rapid timescale, inhibitory nature, and because the pathways for gut-brain communication are disrupted in a brain slice. While the AgRP neuron response to the sensory detection of food is rescued with the onset of weight loss, neural responses to gastrointestinal stimuli are not This combination of changes represents a neural correlate for the long-lasting effects of obesity on the energy homeostasis system
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