Aerobic exercise improves energy and glucose homeostasis through hypothalamic Mitofusion 2‐rescued endoplasmic reticulum stress in diet‐induced obese mice

Abstract Aims Hypothalamic endoplasmic reticulum stress (ERS) and mitochondrial dysfunction are two important mechanisms involved in the pathophysiology of obesity, which can be reversed by aerobic exercise to improve organ function. Mitofusion 2 (Mfn2), a mitochondrial membrane protein, affects both mitochondrial dynamics and ER morphology. This study explored the contribution of hypothalamic Mfn2 to exercise‐induced improvements in energy homeostasis and peripheral metabolism and the underlying mechanisms involved. Materials and Methods We determined the effects of aerobic exercise on energy metabolism and the expression of Mfn2 and α‐MSH in the hypothalamus of diet‐induced obesity (DIO) model mice. In addition, hypothalamic ER signalling and insulin signalling in both the hypothalamus and the liver were evaluated following 4 weeks of aerobic exercise. By using an adenovirus carrying shRNA‐Mfn2, we further explored the effects of hypothalamic Mfn2 on exercise‐induced improvements in energy metabolism, ER signalling and insulin signalling. Results Energy metabolism was obviously improved following 4 weeks of aerobic exercise in DIO model mice. However, after hypothalamic Mfn2 knockdown, the effects of exercise on food intake and peripheral metabolism were significantly suppressed. Hypothalamic ER signalling was attenuated significantly, whereas both hypothalamic and hepatic insulin signalling were obviously activated following aerobic exercise. Nevertheless, exercise‐induced improvements in ER signalling and insulin signalling were attenuated significantly after Mfn2 knockdown. Conclusion These data indicate that aerobic exercise improves whole‐body metabolism in DIO mice, probably via increased hypothalamic Mfn2, which could be further mediated by attenuated HFD‐induced ER stress in the hypothalamus.