Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

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.

Interplay Between Systemic Metabolic Cues and Autonomic Output: Connecting Cardiometabolic Function and Parasympathetic Circuits

“…While a significant amount of research is appropriately dedicated to investigating the role of long-term high fat diet and ultimately the obesity that follows long term consumption of these diets, there is increasing evidence that consumption of high fat for a few days can affect neuronal function. Part of this reevaluation includes the emerging concept that metabolic challenges lead to neural adaptions, rendering the brain insensitive to future metabolic cues ( Beutler et al, 2020 ; Mazzone et al, 2020 ). Importantly, some aspects of adaptive neural plasticity occur quickly, for example after a single bout of exercise ( He et al, 2018 ).…”

Metabolic-sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

“…Whether or not this plays an important role in obesity remains to be determined since obesity desensitizes AgRP neurons to food cues and metabolic feedback 52 . However, the observation that fasting increases NAc dopamine release in response to high fat diet, when compared to chow diet 15 , suggests that homeostatic circuits might play an important role in the pathogenesis of obesity.…”

Monitoring In Vivo Neural Activity to Understand Gut–Brain Signaling

“…Significant advantages include the ability to easily express calcium indicators in genetically defined cell types (using Cre-recombinase–expressing experimental animals) and to record from the same neurons across time, often for weeks or months. The latter is especially important to examine, for example, the neural association of sensory and nutritive information over time ( 37 ), or the long-term effects of diet on in vivo neural activity ( 38-40 ). Limitations of calcium imaging include the relatively slow temporal dynamics of GCaMP relative to other techniques (see below), as well as the inability to directly correlate in vivo increases in calcium with action potentials.…”

“…This attenuated effect is observed after 2 weeks on high-fat diet (prior to significant elevations in body weight), and is more robust after 12 weeks ( 40 ). Second, 2 recent studies used fiber photometry to examine how obesity influences AgRP neuron activity ( 38 , 39 ). Maintenance on high-fat diet causes an attenuation of AgRP neuron inhibition in response to food, gastrointestinal hormones, and intragastric fat (but not sugar).…”