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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., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, β-hydroxybutyrate (βHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with βHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with β-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Key Points: Mice are commonly housed at room temperatures below their thermoneutral zone meaning they are exposed to chronic thermal stress. Endurance exercise induces browning and mitochondrial biogenesis in white adipose tissue of rodents, but there are conflicting reports of this phenomenon in humans. We hypothesized that the ambient room temperature at which mice are housed could partially explain these discrepant reports between humans and rodents. We housed mice at room temperature or thermoneutrality and studied their physiological responses to acute and chronic exercise. We found that thermoneutral housing altered running behaviour and glucose homeostasis, and further, that exercise-induced markers of mitochondrial biogenesis and the browning of white adipose tissue were reduced in mice housed at thermoneutrality., Abstract: Mice are often housed at temperatures below their thermoneutral zone resulting in compensatory increases in thermogenesis. Despite this, many studies report housing mice at room temperature (RT), likely for the convenience of the researchers studying them. As such, the conflicting reports between humans and rodents regarding the ability of exercise to increase mitochondrial and thermogenic markers in white adipose tissue may be explained by the often-overlooked variable, housing temperature. To test this hypothesis, we housed male C57BL/6 mice at RT (22°C) or thermoneutrality (TN) (29°C) with or without access to a voluntary running wheel for 6 weeks or subjected them to an acute exhaustive bout of treadmill running. We examined the gene expression and protein content of select mitochondrial and thermogenic markers in skeletal muscle, epididymal white adipose tissue (eWAT), inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). We also assessed adipocyte morphology and indices of glucose homeostasis. Housing temperature influenced glucose tolerance and insulin action in vivo, yet the beneficial effects of exercise, both acute and chronic, remained intact in eWAT, BAT and skeletal muscle irrespective of housing temperature. Housing mice at TN led to an attenuation of some of the effects of exercise on iWAT. Collectively, we present data characterizing the acute and chronic metabolic adaptations to exercise at different housing temperatures and demonstrate, for the first time, that temperature influences the ability of exercise to increase markers of mitochondrial biogenesis and the browning of white adipose tissue., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)