Ketogenic diet-induced weight loss occurs independent of housing temperature and is followed by hyperphagia and weight regain after cessation in mice.

Ketogenic diets (KDs) are a popular tool used for weight management. Studies in mice have demonstrated that KDs reduce food intake, increase energy expenditure and cause weight loss. These studies were completed at room temperature, a condition below the animal's thermal neutral zone which induces thermal stress. As energy intake and expenditure are sensitive to environmental temperature it is not clear if a KD would exert the same beneficial effects under thermal neutral conditions. Adherence to restrictive diets is poor and consequently it is important to examine the effects, and underlying mechanisms, of cycling from a ketogenic to an obesogenic diet. The purpose of the current study was to determine if housing temperature impacted the effects of a KD in obese mice and to determine if the mechanisms driving KD-induced weight loss reverse when mice are switched to an obesogenic high fat diet. We demonstrate that KD-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are not dependent upon housing temperature. KD-induced weight loss seems to be largely explained by reductions in caloric intake while cycling mice back to an obesogenic diet following a period of KD feeding leads to hyperphagia-induced weight gain. Collectively, our results suggest that prior findings with mice fed a KD at room temperature are likely not an artifact of how mice were housed and that initial changes in weight when transitioning from an obesogenic to a ketogenic diet or back are largely dependent on food intake. KEY POINTS: Ketogenic diets reduce food intake, increase energy expenditure and cause weight loss in rodents Prior preclinical studies have been completed at room temperature, a condition which induces thermal stress and limits clinical translatability Here it is demonstrated that ketogenic diet-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are similar in mice housed at room temperature or thermal neutrality Ketogenic diet-induced reductions in food intake appear to explain a large degree of weight loss. Similarly, switching mice from a ketogenic to an obesogenic diet leads to hyperphagia-mediated weight gain.