Increasing energy expenditure through exercise and low ambient temperature offers oxidative protection to the hypothalamus after high‐fat feeding to mice

Abstract The effects of weight loss produced by increased energy expenditure on measures of oxidative stress and mitochondrial damage have not been investigated in the hypothalamus of diet‐induced obese mice. The present study aimed to characterize the effects of either a low housing temperature of 17°C or daily exercise on a treadmill on high‐fat diet (HFD)‐induced abnormalities in the hypothalamic tissue of mice. Exercise and low ambient temperature protocols were designed to produce energy deficit through increased energy expenditure. Forty mice aged 8 weeks were assigned to one of four conditions: chow diet ( n = 10), HFD ( n = 10), HFD and 5 weeks of either exercise training (ET; n = 10) or an ambient temperature of 17°C ( n = 10). Mice were killed at the age of 31 weeks. In comparison with HFD treatment alone, both interventions reduced body adiposity (14.6% and 27.6% reduction for the ET and 17°C groups, respectively). Moreover, exposing obese mice to ET and 17°C restored mitochondrial DNA content (41.3% and 32.6% increase for the ET and 17°C groups, respectively), decreased level of lipid peroxidation as assessed by the detection of 4‐hydroxy‐nonenal protein adducts (12.8% and 29.4% reduction for the ET and 17°C groups, respectively) and normalized the expression levels of proinflammatory cytokines ( Tnfα : 73.9% and 62%; Il1β : 54.5% and 39.6%; Il6 : 33.1% and 35.6% reduction for the ET and 17°C groups, respectively), as well as several proteins associated with mitochondrial respiratory chain (OxPhos Complex I: 75.7% and 53.9%; Complex III: 33% and 36%; Complex V: 42% and 36.9% reduction for the ET and 17°C groups, respectively) in hypothalamic cells. Negative energy balance induced through either lower ambient temperature or exercise resulted in substantial and similar improvements in markers of inflammation and mitochondrial damage in the hypothalamus of mice with diet‐induced obesity, potentially by reducing oxidative stress.