Intermittent Fasting of High‐Fat Diet Increases Hypothalamic Norepinephrine and Improves Metabolic Parameters in Obese Mice

Abstract

Alternate day, intermittent fasting (IMF) can promote weight loss in obese individuals. We investigated the metabolic and neural mechanisms of IMF in diet‐induced obese mice. Twenty‐four C57 male mice at PND 49 were fed a high‐fat diet (HFD; 45% fat, 20% protein, 35% CHO) ad libitum for 8 wks. Following this, for 4 wks, mice (n = 8/group) were maintained on ad libitum HFD, received IMF of HFD (IMF‐HFD), or were switched to ad libitum low‐fat diet (LFD;10% fat, 20% protein, 70% CHO). Body weight and cumulative calorie intake were not different between the IMF‐HFD and LFD. Indeed, both groups had reduced cumulative caloric intake (~13% for both; p < 0.01) and reduced body weight (~10% for both; p < 0.05) compared with the HFD. Metabolic parameters, however, were different between the IMF‐HFD and LFD groups. Insulin tolerance was improved in IMF‐HFD compared with the HFD group (‐ 20% glucose AUC; p < 0.05), but impaired compared with LFD (+ 22% glucose AUC; p<0.05). Following a fast (8 h), ketone bodies were elevated in IMF‐HFD compared with HFD (p < 0.05) and LFD (p = 0.05). Indirect calorimetry revealed lower RER in IMF‐HFD compared with HFD (p<0.001), but higher than LFD (p<0.05). Hypothalamic tissue homogenates indicated higher levels of norepinephrine in the paraventricular nucleus region of IMF‐HFD compared with HFD (+40.6%, p<0.05) and LFD (+31%, p = 0.05) animals. Thus, while IMF‐HFD reduces body weight and calorie intake similar to a LFD, weight loss by IMF produces distinct metabolic and neural alterations.