Short‐term methionine deprivation improves metabolic biomarkers of obesity

Abstract

Obesity has become an epidemic in the United States and worldwide. Obesity, along with its associated metabolic disorders, predisposes patients to two major types of chronic diseases: diabetes and cardiovascular diseases, and is a threat to our economy and healthcare system. New strategies to combat obesity are urgently needed. Recent studies in mice and humans have found that dietary methionine restriction produces many beneficial effects on metabolic health including reduced adiposity, improved glycemic control and lipid homeostasis. However, the difficulty of long term adherence to a methionine‐restricted diet limits its translational potential as an obesity treatment. To address this problem, we propose that short‐term methionine deprivation serves as a rapid and more effective alternative to treat obesity and its associated metabolic disorders.To determine the impact of methionine deprivation on metabolic health, we placed C57BL/6J mice on a methionine‐free diet for five weeks. We observed that methionine deprivation results in progressive weight loss over five weeks with body composition analysis revealing a profound reduction in fat, with less pronounced decreases in lean and total body mass. This indicates that methionine deprivation is an effective approach to reduce adiposity. After two weeks of diet feeding, calorimetry‐based metabolic chamber experiments indicated that mice fed 0Met diet have increased food consumption and heat production (normalized to body weight), decreased voluntary movement, and improved metabolic flexibility as reflected by a greater shift between the daytime respiratory exchange ratio (RER) and nighttime RER. Analysis of glycemic control by glucose, insulin and pyruvate tolerance test indicates that methionine deprivation is effective in improving glucose tolerance and hepatic insulin sensitivity. To evaluate the potential of short‐term methionine deprivation as a strategy to treat obesity, we examined the metabolic effects of short‐term methionine deprivation in a high‐fat‐diet‐induced obesity. Five weeks of methionine deprivation not only significantly reduced the adiposity induced by high‐fat‐diet feeding, but also corrected hyperglycemia, hyperinsulinemia, dyslipidemia. At the transcriptional level, we found that short‐term methionine deprivation produced a coordinated transcriptional remodeling of genes involved in lipid metabolism, reflected by downregulation of lipogenesis and upregulation of fatty acid oxidation in the liver and a simultaneous upregulation of lipogenesis and fatty acid oxidation in adipose tissue. Molecular signaling analysis revealed downregulation of eIF2α signaling and mTORC1 signaling in both liver and muscle. Collectively, our study demonstrates that short‐term dietary deprivation of methionine produces many similar, but more profound metabolic benefits than long‐term methionine restriction. As such, we propose that this dietary strategy could be used as an adjunct treatment for obesity and obesity‐related disorders such as type 2 diabetes.Support or Funding InformationThis study is supported by a K99/R00 Pathway to Independence Award to D.W.L. from the NIH/National Institute on Aging (AG041765)