Trends in Endocrinology and Metabolism最新文献

Body composition impacts female fertility and there are established relationships between adipose tissue and the reproductive system. Maintaining functional adipose tissue is vital for meeting the energetic demands during the reproductive process, from ovulation to delivery and lactation. White adipose tissue (WAT) shows plastic responses to daily physiology and secretes diverse adipokines that affect the hypothalamic-pituitary-ovarian axis, but many other interorgan interactions remain to be determined. This review summarizes the current state of research on the dialogue between WAT and the female reproductive system, focusing on the impact of this crosstalk on ovarian and endometrial factors essential for fecundity.

Intermittent fasting (IF) modifies cell- and tissue-specific immunometabolic responses that dictate metabolic flexibility and inflammation during obesity and type 2 diabetes (T2D). Fasting forces periods of metabolic flexibility and necessitates increased use of different substrates. IF can lower metabolic inflammation and improve glucose metabolism without lowering obesity and can influence time-dependent, compartmentalized changes in immunity. Liver, adipose tissue, skeletal muscle, and immune cells communicate to relay metabolic and immune signals during fasting. Here we review the connections between metabolic and immune cells to explain the divergent effects of IF compared with classic caloric restriction (CR) strategies. We also explore how the immunometabolism of metabolic diseases dictates certain IF outcomes, where the gut microbiota triggers changes in immunity and metabolism during fasting.

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.

Nicotinamide adenine dinucleotide (NAD⁺) is an essential coenzyme for redox reactions and regulates cellular catabolic pathways. An intertwined relationship exists between NAD⁺ and mitochondria, with consequences for mitochondrial function. Dysregulation in NAD⁺ homeostasis can lead to impaired energetics and increased oxidative stress, contributing to the pathogenesis of cardiometabolic diseases. In this review, we explore how disruptions in NAD⁺ homeostasis impact mitochondrial function in various cardiometabolic diseases. We discuss emerging studies demonstrating that enhancing NAD⁺ synthesis or inhibiting its consumption can ameliorate complications of this family of pathological conditions. Additionally, we highlight the potential role and therapeutic promise of mitochondrial NAD⁺ transporters in regulating cellular and mitochondrial NAD⁺ homeostasis.

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.

Very-low-density lipoprotein (VLDL), a triglyceride-rich lipoprotein secreted by hepatocytes, is pivotal for supplying peripheral tissues with fatty acids for energy production. As if walking on a tightrope, perturbations in the balance of VLDL metabolism contribute to cardiometabolic dysfunction, promoting pathologies such as cardiovascular disease (CVD) or metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the advent of lipid-lowering therapies, including statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, risks for cardiovascular events persist. With limitations to currently available CVD therapeutics and no US Food and Drug Administration (FDA)-approved treatment for MASLD, this review summarizes the current understanding of VLDL metabolism that sheds light on novel therapeutic avenues to pursue for cardiometabolic disorders.

Liver diseases represent a growing global health challenge, and the increasing prevalence of obesity and metabolic disorders is set to exacerbate this crisis. To meet evolving regulatory demands, patient-specific in vitro liver models are essential for understanding disease mechanisms and developing new therapeutic approaches. Organoid models, which faithfully recapitulate liver biology, can be established from both non-malignant and malignant liver tissues, offering insight into various liver conditions, from acute injuries to chronic diseases and cancer. Improved understanding of liver microenvironments, innovative biomaterials, and advanced imaging techniques now facilitate comprehensive and unbiased data analysis, paving the way for personalised medicine. In this review, we discuss state-of-the-art patient-derived liver organoid models, recent technological advancements, and strategies to enhance their clinical impact.

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.

Our limited understanding of metabolic aging poses major challenges to comprehending the diverse cellular alterations that contribute to age-related decline, and to devising targeted interventions. This review provides insights into the heterogeneous nature of cellular metabolism during aging and its response to interventions, with a specific focus on cellular heterogeneity and its implications. By synthesizing recent findings using single-cell approaches, we explored the vulnerabilities of distinct cell types and key metabolic pathways. Delving into the cell type-specific alterations underlying the efficacy of systemic interventions, we also discuss the complexity of integrating single-cell data and advocate for leveraging computational tools and artificial intelligence to harness the full potential of these data, develop effective strategies against metabolic aging, and promote healthy aging.

Glucocorticoids (GCs) are potent anti-inflammatory drugs. A new study by Auger et al. found that GCs increase itaconate, an anti-inflammatory tricarboxylic acid (TCA) cycle intermediate, by promoting movement of cytosolic pyruvate dehydrogenase (PDH) to mitochondria. Itaconate was sufficient for mediating the anti-inflammatory effects of GCs in mice, overriding the notion that nuclear glucocorticoid receptor (GR) is necessary for inflammation inhibition.