News & Views in 2022

New research shows that a drug conjugate that links the dual PPAR𝛼/𝛾 agonist tesaglitazar to a GLP-1 receptor agonist has superior effects on weight loss and glucose metabolism compared with monotherapy in mice. The conjugate has actions in the hypothalamus that may contribute to its benefits.

Adipose tissue plays a critical role in systemic metabolism. This work describes how perturbations in the adipocyte progenitor cell repertoire during the perinatal period exert long-lasting metabolic effects in adulthood.

New research reports that targeting the asialoglycoprotein receptor (ASGR1) in mice promotes cholesterol excretion through a mechanism involving stabilization of LXR without lipogenesis activation, strengthening the idea of therapeutically targeting ASGR1 to lower blood cholesterol and risk of atherosclerotic cardiovascular disease.

Longer duration of breastfeeding is shown to have long-lasting effects in rodents, which lead to an adult phenotype that is resistant to diet-induced obesity and has increased brown adipose tissue activity through a process dependent on hypothalamic FGF21 signalling.

Methanol is a promising feedstock owing to its low price, abundance, energy richness and renewability. However, the toxicity of methanol limits methanol-based biomanufacturing. Rescuing methylotrophic yeast from cell death by restoring phospholipid metabolism enables high-level production of free fatty acids from methanol.

Ultraviolet radiation exerts differential effects in men and women. Parikh et al. reveal that solar exposure on the skin triggers food-seeking behaviour in males, but not females, through a mechanism dependent on ghrelin secretion from skin adipocytes.

Anti-PD-1 immunotherapy has emerged as a revolutionary therapeutic strategy against cancer. However, it often leads to undesired side effects. In this issue, a new study reports how PD-1 signalling drives metabolic dysregulation in colonic lymphoid tissue inducer cells, thus contributing to the development of intestinal inflammation.

Hepatic inflammation is a major co-morbidity in obesity. New work shows that activated brown adipose tissue releases maresin-2, a lipid molecule derived from docosahexaenoic acid, which targets the liver and actively protects against obesity-induced hepatic inflammation.

NAD⁺ is a key electron acceptor in proliferating cells, needed to increase biomass. Computational and experimental approaches demonstrate that NAD⁺ regeneration is critical for de novo lipid synthesis when exogenous sources are limited, underlying cancer cell dependence on lipids when mitochondrial respiration is reduced.

Ong et al. uncover a role for the YAP/TAZ–TEAD transcriptional pathways in retinal angiogenesis via the regulation of amino acid transporters and assessed mTORC activation. These findings establish the mechanism through which endothelial cells regulate nutrient acquisition and consumption.

Itaconate is an immunomodulatory Krebs cycle-derived metabolite. Description of two isomers of itaconate, mesaconate and citraconate, which have overlapping and distinct properties when compared with itaconate in macrophages, expands the knowledge of this intriguing family of immunomodulatory metabolites.

Activation of resting regulatory T cells (T_regs) upon antigen encounter is essential for proper T_reg function. However, the metabolic pathways that mediate this transition are unknown. Liu et al. have identified the non-oxidative pentose phosphate pathway as a central regulator of T_reg activation and function.

A glucose-like metabolite, which is reduced in the serum of diabetic patients, inhibits the entry of SARS-CoV-2 into key cellular targets. The work led by Cheng and colleagues provides a molecular explanation for the increased risk of severe COVID-19 in patients with diabetes.

Until now, the BDNF–TrkB signalling pathway was thought to be exclusively regulated by neurons. Ameroso et al. show that astrocytic TrkB.T1 is a critical substrate of BDNF in the regulation of energy balance and that its defective signalling in hypothalamic circuits leads to obesity.

Although food-craving episodes during pregnancy are common in humans, the neural, cellular and molecular mechanisms that underlie these eating bouts remain unknown. New work points to dopamine receptor D2-expressing neurons of the reward system as critical mediators of compulsive feeding during pregnancy.

Oncometabolites are pro-tumourigenic metabolites that can determine tumour aggressiveness. This study found that methylmalonic acid is upregulated in breast lung metastasis and metastatic cancer cells. Methylmalonic acid alters the gene expression profile to induce a pro-metastatic phenotype in breast and lung cancer cells.

The clearance of dying cells by macrophages releases mediators that switch off inflammation. Ampomah et al. reveal how an amino acid derived from apoptotic cargo changes the methylation epigenome of macrophages to take the brakes off an ERK-dependent pathway that terminates inflammatory responses.

Multi-organ disease in patients seriously unwell with COVID-19 is commonly reported. However, debate exists as to whether extra-pulmonary manifestations are the result of indirect effects or of direct extra-pulmonary organ infection. Wanner et al. attempt to tackle this issue with a focus on liver tropism of the SARS-CoV-2 virus.

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.

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.