Longitudinal Metabolic Phenotyping in Mice Reveals Feeding Behaviors Associated with Weight Gain and Uncovers a Brainstem Circuit that Modulates Colitis Associated Bodyweight Loss

Abstract

We longitudinally assessed changes in metabolic parameters and feeding behaviors in male and female mice switched to obesogenic 45% or 60% high-fat diets (HFD) over multiple weeks. HFD fed mice experience chronic caloric hyperphagia coupled with attempts to restore caloric intake over the first two-weeks of diet exposure but is then lost leading to weight gain. Energy expenditure rapidly increases but does not account for excess caloric intake resulting in chronic positive energy balance. HFD exposure causes rapid, sustained increases in meal numbers and per meal calories suggesting impairments in both satiation and satiety. Running wheel access increases energy expenditure and blunts weight gain for two-weeks following HFD feeding but is not sustained. Since HFD feeding rapidly impaired satiation we aimed to evaluate the influence of HFD feeding on hindbrain neurons that impact satiation. Preproglucagon neurons reside in the hindbrain, regulate satiation, express the interleukin-6 receptor (IL6R), and functionally respond to IL-6. While L-6 levels are chronically elevated in obesity, the physiological relevance of PPG-IL6R signaling has not been explored. Loss of PPG neuron IL-6R (PPG-IL6R KO) results in protection against HFD induced impairments in satiation but has no effect on weight gain. We tested whether increases in food intake may promote fitness in models of infection associated inflammation. Colitis induction in PPG-IL6R KO exacerbated bodyweight loss and impaired recovery relative to controls. Bodyweight differences were driven by an inability to increase meal sizes and maintain energy expenditure in PPG-IL6R KO mice. Loss of afferent neuron IL-6 expression also leads to exacerbated colitis induced bodyweight loss. Our findings uncover a novel interoceptive circuit that may convey organ specific peripheral inflammation to hindbrain neurons to protect against excess sickness induced bodyweight loss.