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Obesity affects a significant fraction of the world population, with some states or countries reporting overwhelming majority of the population as obese or overweight. Effective treatments were not readily available until the recent approval of glucagon-like peptide-1 (GLP-1) -based pharmacotherapeutics for weight loss. Since then, the use of GLP-1-based pharmacotherapies for the treatment of obesity has skyrocketed. In addition to or because of the effective weight loss, these medications affect many different organs in the body. Many of these effects, including the degree of weight loss achieved, show significant sex differences. Moreover, recent analysis of online patient communities identified a range of self-reported reproductive and endocrine side effects of GLP-1 based therapies including menstrual irregularities, reduced libido, and hot-flashes that have not been systematically captured in clinical trials. Some of these reports contrast with recent data indicating that in Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly Polycystic Ovary Syndrome) patients semaglutide-associated weight loss normalizes menstrual cycles in most patients, leaving this issue unresolved. While it has been established that sex and sex hormones affect the action of GLP-1 analogues, whether these medications affect the levels of sex hormones and reproductive organs is less well understood, especially in a chronic and clinically relevant drug application setting.

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Intermittent time-restricted feeding recapitulates the physiological benefits of daily time-restricted feeding in male mice with chronic metabolic disease

Andre Sarmento-Cabral, Marta G. Novelle, Luz Marina Sánchez-Mendoza, Natalia Herman-Sanchez, ... Alberto Diaz-Ruiz

Intermittent time-restricted feeding recapitulates the physiological benefits of daily time-restricted feeding in male mice with chronic metabolic disease

Time-restricted feeding (TRF) is proposed as a relevant strategy to counteract obesity and metabolic disorders; however, the therapeutic efficacy of more pragmatic intermittent TRF (iTRF) regimens remains undefined. Herein, daily and intermittent TRF significantly improved whole-body physiology, promoted key hallmarks of energy restriction, and induced coordinated transcriptional and lipidomic remodeling in male mice with chronic metabolic dysfunction previously established by prolonged high-fat, high-cholesterol, high-fructose feeding. These effects were summarized using three composite scores capturing physiological/metabolic, energy restriction, and lipidic responses, which consistently separated daily and intermittent TRF regimens from ad libitum-fed mice. Lipidomic profiling identified a subset of hepatic lipids associated with systemic health, pointing to lipid remodeling, particularly at the endoplasmic reticulum, as a potential feature of the TRF response. Notably, TRF failed to histologically improve hepatic steatosis, ballooning, or inflammation, and its overall benefits were clearly inferior to dietary normalization to standard chow diet. Altogether, these data (i) demonstrate that intermittent TRF recapitulates the beneficial effects in advanced metabolic disease, (ii) provides translational support for flexible TRF strategies, and (iii) highlights the need to integrate TRF with additional therapeutic strategies.

Articles in Press

Intermittent time-restricted feeding recapitulates the physiological benefits of daily time-restricted feeding in male mice with chronic metabolic disease

Andre Sarmento-Cabral, Marta G. Novelle, Luz Marina Sánchez-Mendoza, Natalia Herman-Sanchez, ... Alberto Diaz-Ruiz

Intermittent time-restricted feeding recapitulates the physiological benefits of daily time-restricted feeding in male mice with chronic metabolic disease

Time-restricted feeding (TRF) is proposed as a relevant strategy to counteract obesity and metabolic disorders; however, the therapeutic efficacy of more pragmatic intermittent TRF (iTRF) regimens remains undefined. Herein, daily and intermittent TRF significantly improved whole-body physiology, promoted key hallmarks of energy restriction, and induced coordinated transcriptional and lipidomic remodeling in male mice with chronic metabolic dysfunction previously established by prolonged high-fat, high-cholesterol, high-fructose feeding. These effects were summarized using three composite scores capturing physiological/metabolic, energy restriction, and lipidic responses, which consistently separated daily and intermittent TRF regimens from ad libitum-fed mice. Lipidomic profiling identified a subset of hepatic lipids associated with systemic health, pointing to lipid remodeling, particularly at the endoplasmic reticulum, as a potential feature of the TRF response. Notably, TRF failed to histologically improve hepatic steatosis, ballooning, or inflammation, and its overall benefits were clearly inferior to dietary normalization to standard chow diet. Altogether, these data (i) demonstrate that intermittent TRF recapitulates the beneficial effects in advanced metabolic disease, (ii) provides translational support for flexible TRF strategies, and (iii) highlights the need to integrate TRF with additional therapeutic strategies.

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