Yo-Yo Dieting: Mixed Messages for β-Cell Plasticity

Weight management in individuals with obesity is a firstline lifestyle intervention to prevent worsening of insulin resistance, progression to type 2 diabetes (T2D), and adverse cardiovascular disease outcome. However, persistent weight reduction is often hard to maintain, with <6% of subjects able to achieve sustained weight loss during a 15-year follow-up (1). Current evidence suggests that repeated weight loss and subsequent gain, a phenomenon known as weight cycling or “yo-yo dieting,” exacerbates the risk for T2D and cardiovascular disease (2). The full spectrum of its adverse effects and the underlying mechanisms, however, remain poorly understood. In this issue of Diabetes, Winn et al. (3) reveal a surprising consequence of yo-yo dieting on inducing b-cell maladaptation, leading to impaired insulin secretion mismatched for the insulin-resistant peripheral tissue. This work builds upon the initial discovery of weight cycling– induced worsening of peripheral insulin resistance compared with that of similarly obese mice (4). In an insulin-resistant state, b-cells increase insulin secretion to maintain normoglycemia and compensate for the diminished peripheral insulin action. Persistence of insulin resistance leads to eventual decompensation due to b-cell dysfunction, dedifferentiation, and death (5,6). The most intriguing finding of the current study lies in the islet insulin secretion defects upon weight cycling despite impaired peripheral insulin sensitivity comparable to the persistently obese state. This metabolic conundrum suggests that b-cell–intrinsic defects are uniquely induced by weight cycling and exacerbate decompensation (Fig. 1). These defects do not involve diminished glucose responsiveness but instead entail impaired cAMP-dependent secretion and reduced insulin content. Transcriptomic analysis of islets from obese and weight-cycled mice revealed an upregulated replication-related program and downregulation of genes involved in protein localization, b-cell identity, and functional maturity, indicative of a functionally immature b-cell state primed to replicate. However, no corresponding differences in replication were observed. As attempted replication under conditions of stress can trigger cell death (7,8), b-cells subjected to weight cycling may not be survival competent. This notion is supported by a decrease in islet size and area along with reduced b-cell number. Intriguingly, the authors noted induction of Ins1 and Ins2, a potential compensatory response to attenuated b-cell functional mass. As cell cycle genes are involved in DNA repair, differential gene expression in this pathway may reflect an ongoing DNA damage response. Direct assessment of b-cell DNA damage and cell death preceding and during the weight cycling regimen will clarify the mechanisms that underly b-cell decompensation triggered by nutrient fluctuations. What, then, are the signals that drive b-cell maladaptation during weight cycling? Body weight fluctuations evoke nutrient fluxes in metabolic tissues along with altered appetite control in the central nervous system (9), which raises the possibility of interorgan cross talk subserving b-cell defects. Adipose tissue bears the brunt of weight cycling as a major site of lipid storage and mobilization, and its heightened proinflammatory T-cell response contributes to impaired glucose tolerance (4). While the authors found that the cause of weight cycling–induced worsening of glucose tolerance largely lies in b-cell insulin secretion defects, they noted reduced glucose uptake in adipose tissue and muscle. This constellation of metabolic abnormalities highlights the complexity of tissue responses to repeated insults of nutritional overload and deprivation. Weight loss and regain leads to lipolysis and fatty acid re-esterification in adipose tissue (10). Nutritional stress due to lipid overload and hyperglycemia induces b-cell adaptation during weight gain, while subsequent weight loss and the accompanying onslaught of lipolytic mediators could trigger a maladaptive response (11). Metabolome and secretome profiling across multiple tissues at distinct stages of