Articles in 2022

The genetic architecture of polygenic childhood obesity remains poorly understood. New work characterizes the dynamic genetic architecture of childhood BMI during the first 8 years of life by identifying genetic loci involved in the leptin–melanocortin pathway.

Zhang et al. show that the regulation of PDHE1α subcellular localization by a phosphorylation switch coordinates responses to antitumour immune surveillance.

Helgeland et al. characterize genetic loci associated with early childhood body mass index, highlighting roles of genes involved in monogenic obesity, appetite regulation and energy expenditure, many of which show age-specific association patterns.

Core body temperature and metabolic rate have both been proposed to regulate longevity, but their relative contribution had not been determined. Zhao et al. separated the effects of these two parameters in mice and hamsters, revealing that core body temperature is a more important determinant of longevity than metabolic rate.

Healthy white adipose tissue is dependent on the proliferation of endothelial cells to maintain homeostasis or undergo expansion. A new study shows that endothelial cells communicate with adipocytes via polyamines to promote vascularization of adipose tissue, thereby reversing the metabolic effects of obesity.

Endothelial cells in white adipose tissue are shown to produce polyamines, which regulate adipocyte lipolysis, thus demonstrating how local angiocrine signals contribute to healthy adipose tissue homeostasis.

Chen et al. show how host genetics influence the abundance of commensal Akkermansia muciniphila in the gut, which in turn produce palmitoleic acid, thus contributing to shaping host immune responses to Mycobacterium tuberculosis infection.

Zhao et al. uncouple the effects of body temperature and metabolic rate on lifespan in two rodent models, showing that in warm conditions, where body temperature is elevated and metabolic rate reduced, lifespan is reduced. Reversal of increased body temperature reverses the negative impact of high ambient temperatures on lifespan despite lowered metabolic rate.

Fujimaki et al. show that soluble Dll4 from endothelial cells triggers atrophy in myofibres via Notch2 signalling, suggesting Dll4 as a therapeutic target for muscle atrophy.

Fasolino et al. provide insights into ductal cell roles and type 1 diabetes pathogenesis using a pancreatic islet single-cell atlas generated by the Human Pancreas Analysis Program.

Zhong, Wan and Cai et al. show that deficiency of the microsomal prostaglandin E synthase-2 (mPGES-2) in pancreatic β-cells improves glucose metabolism and insulin secretion in mice by inhibiting β-cell senescence and dysfunction during diabetes.

Mutant p53 protein is stabilized by direct binding to 2-HG produced by malic enzyme 2, resulting in enhanced tumour growth.

This Perspective summarizes the ongoing development of CAR-based therapies in indications beyond cancer, including for cardiometabolic diseases, fibrosis, autoimmune diseases and ageing.

Interleukin 6 is a pleiotropic cytokine that can be pro- or anti-inflammatory, depending on the metabolic context. Kistner et al. propose that these context-dependent effects are due to its adaptive role for short-term energy allocation, particularly during physical activity.

GDF15 is a hormone with the potential to regulate energy intake. GDF15 signals via the GFRAL/RET receptor complex, and besides the ligand activation of the receptor complex, our knowledge on control of receptor signalling is limited. Chow et al. show that MT1-MMP controls GDF15 actions by regulating levels of GFRAL.

Although glucose classically serves as the main neuronal fuel source in the brain, Silva et al. demonstrate that ketones produced by local glial cells are critical for memory formation in starving flies. Here we discuss the implications of these findings for aging, neurodegeneration and the genetics of ketone metabolism.

In the Drosophila starved brain, memory formation undergoes adaptive plasticity. Silva et al. show that neurons in the olfactory memory centre of the starved fly are fuelled by glial-derived ketone bodies in order to sustain memory formation.

The GDF15–GFRAL axis is key for regulating energy homeostasis and body weight. Membrane-bound matrix metalloproteinase 14 is shown to negatively regulate GFRAL, whereas its downregulation protects against diet-induced obesity through increased GDF15 signaling.

The creatine/phosphocreatine system is known to have diverse functions in various tissues. Maqdasy, Lecoutre and colleagues reveal a new role, namely, regulating the development of obesity-induced inflammation in white adipocytes.