Intermittent Fasting Promotes Fat Loss with Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice

Clinical studies indicate alternate day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into 4 groups and either maintained on ad libitum HFD (HFD), received alternate day access to HFD (IMF- HFD), switched to ad libitum low fat diet (LFD; 10% fat), or received IMF of LFD (IMF- LFD). After 4 weeks, IMF-HFD (~13%) and IMF-LFD (~18%) had significantly lower body weights than HFD. Body fat was also lower (~40-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (~12-13%) compared with HFD and IMF-HFD groups. Oral glucose tolerance AUC was lower in the IMF-HFD (~50%), whereas insulin tolerance AUC was reduced in all diet interventions (~22-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (~55-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with ad libitum fed groups, whereas NE content was higher (~19-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (~65-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and NPY, suggesting an involvement in the counter regulatory processes of short-term weight loss are associated with an IMF dietary strategy.Peer reviewe