Trends in Endocrinology and Metabolism最新文献

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.

Fasting is a recurrent daily energy stress that benefits healthspan and lifespan. While ketones fuel fasting in vertebrates, the underlying transcriptional mechanism remains incompletely understood. Recently, Korenfeld et al. revealed peroxisome proliferator-activated receptor alpha (PPARα)-dependent enhancer priming as a keystone for ketone production, increasing our understanding of mechanisms underlying metabolic benefits of alternate-day fasting (ADF).

Cardiovascular disease (CVD) remains a significant global health concern, with obesity recognized as a prominent risk factor. The 'obesity paradox' (OP) suggests that obesity does not always lead to adverse outcomes, particularly in heart failure (HF). In this forum, we discuss the relevance of the OP in the current therapeutic landscape for cardiometabolic diseases.

Obesity has become a global pandemic that is associated with a range of metabolic disorders. Traditional treatment options, such as lifestyle modification and anti-obesity medications, often exhibit limited efficacy and can lead to long-term weight gain, especially upon discontinuation of the medication. Although bariatric surgery is effective, its accessibility is constrained, and only a small percentage of eligible patients receive this intervention. Over the past two decades, endoscopic bariatric and metabolic therapies (EBMTs) have emerged as minimally invasive and effective alternatives for managing obesity and its related comorbidities. This article reviews primary gastric and small bowel EBMTs, their mechanisms of action, key supporting literature, and the metabolic outcomes associated with each device and procedure.

Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases. One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes. We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas.

Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.

The Genes & Health study, an initiative focused on British-Pakistani and British-Bangladeshi volunteers, is at the forefront of diversifying genetic research and driving scientific innovation. Here, we explore how this study has propelled scientific advancements and positively impacted communities, emphasizing its collaborative ethos, dedication to societal needs, and accomplishments.

The widespread use of per- and polyfluoroalkyl substances (PFASs), and their resistance to degradation, renders human exposure to them inevitable. PFAS exposure disturbs endocrine function, potentially affecting cognitive development in newborns through thyroid dysfunction during pregnancy. Recent studies reveal varying male and female reproductive toxicity across PFAS classes, with alternative analogs affecting sperm parameters and legacy PFASs correlating with conditions like endometriosis. Metabolically, PFASs exposure is linked to metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and liver toxicity, particularly in early childhood. This review focuses on the endocrine-disrupting impact of PFASs, particularly on fertility, thyroid, and metabolic functions. We highlight the complexity of the PFAS issue, given the large number of molecules and their extremely diverse mixed effects.

Astrocytes, the predominant glial cell type in the mammalian brain, influence a wide variety of brain parameters including neuronal energy metabolism. Exciting recent studies have shown that obesity and diabetes can impact on astrocyte function. We review evidence that dysregulation of astrocytic lipid metabolism and glucose sensing contributes to dysregulation of whole-body energy balance, thermoregulation, and insulin sensitivity. In addition, we consider the overlooked topic of the sex-specific roles of astrocytes and their response to hormonal fluctuations that provide insights into sex differences in metabolic regulation. Finally, we provide an update on potential ways to manipulate astrocyte function, including genetic targeting, optogenetic and chemogenetic techniques, transplantation, and tailored exosome-based therapies, which may lead to improved treatments for metabolic disease.