Nature Reviews Endocrinology最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) is a chronic condition associated with metabolic syndrome, a group of conditions that includes obesity, insulin resistance, hyperlipidaemia and cardiovascular disease. Primary growth hormone (GH) deficiency is associated with MASLD, and the decline in circulating levels of GH with weight gain might contribute to the development of MASLD. Raising endogenous GH secretion or administering GH replacement therapy in the context of MASLD enhances insulin-like growth factor 1 (IGF1) production and reduces steatosis and the severity of liver injury. GH and IGF1 indirectly control MASLD progression by regulating systemic metabolic function. Evidence supports the proposal that GH and IGF1 also have a direct role in regulating liver metabolism and health. This Review focuses on how GH acts on the hepatocyte in a sex-dependent manner to limit lipid accumulation, reduce stress, and promote survival and regeneration. In addition, we discuss how GH and IGF1 might regulate non-parenchymal cells of the liver to control inflammation and fibrosis, which have a major effect on hepatocyte survival and regeneration. Development of a better understanding of how GH and IGF1 coordinate the functions of specific, individual liver cell types might provide insight into the aetiology of MASLD initiation and progression and suggest novel approaches for the treatment of MASLD.

The tuberal hypothalamus regulates a range of crucial physiological processes, including energy homeostasis and metabolism. In this Review, we explore the intricate molecular mechanisms and signalling pathways that control the development of the tuberal hypothalamus, focusing on aspects that shape metabolic outcomes. Major developmental events are discussed in the context of their effect on the establishment of both functional hypothalamic neuronal circuits and brain–body interfaces that are pivotal to the control of metabolism. Emerging evidence indicates that aberrations in molecular pathways during tuberal hypothalamic development contribute to metabolic dysregulation. Understanding the molecular underpinnings of tuberal hypothalamic development provides a comprehensive view of neurodevelopmental processes and offers a promising avenue for future targeted interventions to prevent and treat metabolic disorders.

The prevalence of obesity increases with age but is apparent even in early life. Early childhood is a critical period for development that is known to influence future health. Even so, the focus on obesity in this phase, and the factors that affect the development of obesity, has only emerged over the past two decades. Furthermore, there is a paucity of iterative work in this area that would move the field forward. Obesity is a complex condition involving the interplay of multiple influences at different levels: the individual and biological level, the sociocultural level, and the environmental and system levels. This Review provides a brief overview of the evidence for these factors with a focus on aspects specific to early life. By spotlighting the complex web of interactions between the broad range of influences, both causal and risk markers, we highlight the complex nature of the condition. Much work in the early life field remains observational and many of the intervention studies are limited by a focus on single influences and a disjointed approach to solutions. Yet the complexity of obesity necessitates coordinated multi-focused solutions and joined-up action across the first 2,000 days from conception, and beyond.

Epidemiology studies have demonstrated a clear association between obesity and the development of several distinct malignancies, with excessive visceral adiposity being an increasingly prevalent feature in patients with cancer presenting for therapeutic intervention. Clinical trials and meta-analyses have helped to inform effective and safe dosing of traditional systemically administered anticancer agents in adult patients with cancer and obesity, but there remains much debate not only regarding the effect of obesity on the more novel targeted molecular and immune-based therapies, but also about how obesity is best defined and measured clinically. Low muscle mass is associated with poor outcomes in cancer, and body composition studies using biochemical and imaging modalities are helping to fully delineate the importance of both obesity and sarcopenia in clinical outcomes; such studies might also go some way to explaining how obesity can paradoxically be associated with favourable clinical outcomes in certain cancers. As the cancer survivorship period increases and the duration of anticancer treatment lengthens, this Review highlights the challenges facing appropriate treatment selection and emphasizes how a multidisciplinary approach is warranted to manage weight and skeletal muscle loss during and after cancer treatment.

Multiple sclerosis (MS) targets the myelin sheath of central nervous system (CNS) neurons. MS is initiated by autoreactive CD4⁺ T cells, and obesity is known be associated with an increased risk of MS, particularly in women. A study in Cell Metabolism now identifies a female-specific mechanism by which obesity increases the risk of MS by promoting a pro-inflammatory T helper 1 (T_H1) CD4⁺ T cell phenotype.

To investigate these sex-dependent inflammatory signatures further, the researchers used a diet-induced-obesity (DIO) mouse model combined with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS in which T cells are autoreactive against myelin. EAE progression and symptoms were exacerbated to a greater extent by DIO (compared with normal-weight EAE controls) in female compared with male mice.