Challenging dogmas, Prentki et al. propose an alternative paradigm of obesity-related type 2 diabetes, interpreting insulin resistance, reduced glucose-induced insulin secretion, mild hyperglycemia, and glucosuria not as primary pathological abnormalities but as beneficial allostatic responses to nutrient excess. Therapeutic strategies should focus on glucose fate, not blood glucose levels alone.

Population-level nuclear magnetic resonance (NMR)-based lipoprotein profiling is a key tool for investigating dysregulated lipoprotein metabolism and its role in cardiovascular disorders. However, associations with size-resolved lipoprotein composition readouts are difficult to dissect, as these traits are often highly correlated. Derived variables can therefore be more relevant to biological interpretation. Here, we show that the total fatty acid (FA) content of the lipoproteins derived from their lipid headgroup concentrations using the formula FA = 3TG + 2PL + CE strongly correlates (Spearman rho = 0.98) with the independently measured total fatty acid content. This observation is not self-evident since these variables are determined using different portions of the NMR spectrum. Using NMR data acquired on the Nightingale platform for 274,303 UK Biobank (UKB) participants and genetic associations as a readout, we then show that this relationship also holds at the size-resolved lipoprotein level. We identified eight gene loci where the proposed FA variables display a significantly stronger genetic association signal than that of the corresponding lipid headgroup variables. Five of these loci (LIPC, LIPG, PLB1, LPL, and APOC3) have a direct function in FA metabolism. Including computed size-resolved FA variables may therefore improve the biological interpretation of future studies based on Nightingale’s data.

Grandl et al. reveal a novel physiological role of FGF21 as a hormone of protein folding stress. They show that FGF21 enhances but does not initiate the unfolded protein response and integrated stress response via increased enzymatic sulfide production, thereby improving stress resilience and reducing ER stress.

Incretin-based therapies are transforming the treatment of obesity and related comorbidities. This Review outlines the current landscape of obesity drug development, focusing on glucagon-like peptide ...

Summary: The call to arms for alternatives to model organisms of disease will fail without ongoing integration with – and validation against – complex animal models and support from the animal modelli...

Lin et al. reveal that FGF21 acts on the hindbrain (nucleus of the solitary tract [NTS] and area postrema [AP]), and not the hypothalamus, to reduce body weight. Specifically, FGF21 signaling to the h...

Abstract. Glucagon is a peptide hormone mainly secreted by the alpha cells of the pancreatic islets in response to nutritional stimuli. Traditionally recog

Nature Reviews Cardiology - In this Review, De Blasio and Ritchie describe the inflammatory pathways involved in the pathogenesis of diabetic cardiomyopathy and discuss potential strategies to...

The biological reason why mammals increase daily energy expenditure when consuming a protein-dilute diet is currently enigmatic. Recognizing that body…

The NIH has recently called for expanding use of new approach methodologies (NAMs) to reduce use of animals in research. Arany discusses the need not to forget the irreplaceable aspects of animal research and their fundamental importance to biomedical advancement.

Health Secretary Robert F. Kennedy Jr. has announced new dietary guidelines for Americans focused on promoting whole foods, healthy proteins and fats. And he has "declare[d] war" on added sugar.

Neurons are shown to use fatty acid β-oxidation as a fuel source for memory formation upon intensive learning in Drosophila, challenging the view that neurons are unable to use fatty acids for energy ...

Calcium imaging of taste neurons and the ventral brain provides insight into evolutionary divergence of food choice in Drosophila species, supporting a role of sensorimotor processing in addition to p...

In these financially straitened times, funders must recognize that great discoveries often arise from work that was looking for something completely different.

Single-cell metabolomics (SCM) can probe metabolic heterogeneity but is hindered by low sensitivity for small molecules, limited scalability, and the lack of standardized frameworks for data analysis....

A famous graphic, now updated, compares locomotion in the animal kingdom

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stres...

Nature Metabolism, Published online: 24 September 2025; doi:10.1038/s42255-025-01360-4The authors highlight inconsistencies and divergencies in the literature reporting data on indirect calorimetry for studies on whole-body energy homeostasis, and propose harmonization of standards to facilitate data comparison and interpretation across different datasets.

ALT: a gold trophy with a laurel wreath around it and the words well done on a gold ribbon

Recent Advances and Controversies in the Measurement of Energy Metabolism

Loss of lean mass is a potential concern for semaglutide-induced weight loss. This study indicates that semaglutide has unexpected effects on skeletal muscle mass and strength in mice, demonstrating a...

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

The data on high protein diets, bars, supplements, and powders will surprise you

Studies in mice show that acute stress activates hyperglycaemia via activation of a medial amygdala–ventral hypothalamic circuit that controls glucose metabolic responses in the liver, independen...

Using cryo-electron microscopy, the interactions of Sestrin2 and CASTOR1 with GATOR2 were resolved, revealing how mTORC1 activation is regulated and how nutrient availability triggers signalling for cellular growth.

Caloric restriction improves Alzheimer’s Disease outcomes in mice, but this diet not only reduces calories, but imposes a prolonged fast between meals. Here, the authors show this fast is essential to...

Imidazole propionate produced by gut microbiota is associated with atherosclerosis in mouse models and in humans, and causes the development of atherosclerosis through activation of the imidazoline-1 ...

By combining structural biology and evolutionary genomics analyses, the evolution of enzymes over 400 million years is shown to be governed by catalytic function, metabolic network architecture, cost ...

Diets that are high in fat cause overeating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause ob…

A robust dose–response relationship between bodyweight loss and diabetes remission was observed, independent of age, diabetes duration, HbA1c, BMI, and type of intervention. These findings highlight t...

imageimagePathway-focused metabolite ratio-based analysis of 49 tumor and 8 normal epithelial cell lines grown in their respective standard conditions reveals common and distinctive metabolic signatur...

Evidence suggests that incretin-based dual agonist pharmacotherapy is helpful in persons with obesity. Mazdutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, may have efficacy in ...

But eliminating cysteine, which is found in high-protein foods, from human diets would be challenging.

PCSK9 regulates low density lipoprotein-cholesterol import and determines organ preference of metastatic pancreatic ductal adenocarcinoma, with PCSK9-low cells metastasizing to the liver and PCSK9-hig...

Diet can impact anticancer drug activity. A classic example in rodents is a ketogenic diet enhancing PI3K inhibitor activity. Here, we show that phytochemicals and their microbiome derivatives, rather than macronutrient composition, underlie this phenomenon.

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality ...