Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

Department of Ecology and Evolutionary Biology University of California Los Angeles CA USA

Department of Molecular Cell and Developmental Biology University of California Los Angeles CA USA

Department of Surgery Keck School of Medicine University of Southern California Los Angeles CA USA

IFOM FIRC Institute of Molecular Oncology Milano Italy

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Longevity Institute and Davis School of Gerontology University of Southern California Los Angeles CA USA

Molecular Imaging Center Department of Radiology Keck School of Medicine University of Southern California Los Angeles CA USA

Section of Human Anatomy Department of Biomedicine Neuroscience and Advanced Diagnostics University of Palermo Palermo Italy

Translational Gerontology Branch Intramural Research Program of the National Institute on Aging National Institutes of Health Baltimore MD USA

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Nat Rev Endocrinol. 2022 Jan;18(1):1. doi: 10.1038/s41574-021-00594-y. PubMed

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