bims-obesme 2026-03-22 papers

Issue of 2026–03–22
nine papers selected by
Xiong Weng, University of Edinburgh

Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]

Mitochondrial control of glycerolipid synthesis by a PEP shuttle.

Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.

Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.

Keywords: bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity

DOI: https://doi.org/10.1016/j.cell.2026.02.017

Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):

Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.

Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.

Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.

DOI: https://doi.org/10.1038/s41467-026-70399-y

Nat Commun. 2026 Mar 15.

Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis.

Anna Cetnarowska, Mette Hyldahl, Marcus Nygård, Hesam Dashti, Bo Vagner Hansen, Laura Kristine Holm, Kaja Madsen, Maria Stahl Madsen, Vallari Shukla, Esra Durmaz Mitchell, Alexander Rauch, Jesper Grud Skat Madsen, Melina Claussnitzer, Susanne Mandrup.

Transcriptional master regulators drive cell fate transitions. Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis, and its expression must therefore be tightly regulated and efficiently induced in response to adipogenic cues. Here we decipher the regulatory mechanisms of the highly connected enhancer community driving activation of the PPARG locus during adipocyte differentiation of human mesenchymal stem cells. By systematically deleting nine individual enhancers, spanning upstream, promoter-proximal, and downstream super-enhancer constituents, we demonstrate elaborate enhancer crosstalk in cis involving stabilization of C/EBPβ recruitment prior to chromatin remodeling. We show that the super-enhancer constituent E + 102 plays a dual role in cis crosstalk and feedback activation and is obligate for activation of PPARG expression. Non-coding genetic variants associated with cardiometabolic traits and predicted to regulate PPARG expression map to E + 102 and other essential enhancers in the community, thereby supporting the importance of these enhancers in human physiology and disease.

DOI: https://doi.org/10.1038/s41467-026-70401-7

Trends Endocrinol Metab. 2026 Mar 19. pii: S1043-2760(26)00009-3. [Epub ahead of print]

Brown adipose tissue and beyond: lipolysis and glycerolipid cycling in thermogenesis.

Dominique Langin, André C Carpentier.

Following cold exposure, brown adipose tissue (BAT) generates heat through uncoupling protein 1-mediated thermogenesis. Intracellular lipolysis, mediated by neutral lipases, provides nonesterified fatty acids that fuel BAT mitochondrial respiration and uncoupling. In the present review, we provide current knowledge on the neuroendocrine control of intracellular lipolysis in brown adipocytes and discuss how the intracellular lipolytic machinery is important for the thermogenic activity of BAT. We also examine the importance of glycerolipid cycling and white adipose tissue (WAT) lipolysis in cold-induced thermogenesis. We discuss recent evidence suggesting a significant role for other organs, such as the liver and cardiovascular system, in nonshivering thermogenesis. Beyond BAT, interorgan glycerolipid cycling between WAT and lean organs may contribute significantly to whole-body thermogenic responses.

Keywords: adipocyte; brown fat; glycerolipid cycling; lipolysis; liver; thermogenesis

DOI: https://doi.org/10.1016/j.tem.2026.01.009

Cell Metab. 2026 Mar 13. pii: S1550-4131(26)00055-0. [Epub ahead of print]

Large-scale metaproteomics of human gut microbiota reveals microbial functions in metabolic diseases and aging.

The protein-level functionalities of the human gut microbiota in large populations, and their associations with host factors, remain unexplored. This study reports a metaproteomic study of 1,967 fecal samples from 1,399 middle-aged and elderly Chinese individuals, identifying microbial functions linked to 44 phenotypes. We uncover aging-associated functional shifts in carbon metabolism and energy production driven by species within the Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota. Across metabolic diseases, we observe the consistent depletion of Bacillota species and their proteins involved in carbohydrate, energy, amino acid metabolism, and short-chain fatty acid production. We also identify medication-associated features across diabetes, hypertension, and dyslipidemia. Validated in an independent cohort, Megasphaera elsdenii emerged as a hub species in type 2 diabetes. Experimental validation indicates that M. elsdenii is promoted by antidiabetic drugs and may regulate glucose homeostasis through butyrate production. This study provides protein-level evidence of microbial functions in health and disease, highlighting potential therapeutic targets.

Keywords: Megasphaera elsdenii; aging; diabetes; human gut microbiome; metaproteomics

DOI: https://doi.org/10.1016/j.cmet.2026.02.012

Life Metab. 2026 Feb;5(1): loaf038

Aberrant miR-378 expression promotes hepatic lipid accumulation via hijacking the bile acid-regulated autophagy.

Zhoumin Niu, Ying Yan, Wei Liu, Qiuming Yao, Jingjing Chen, Siyi Shen, Jing Yu, Mei Ma, Zhuoyang Li, Yuting Wu, Yan Li, Cheng Hu, Hailuan Zeng, Xin Gao, Yuying Li, Jingjing Jiang, Hao Ying.

Dysregulated autophagy contributes to liver steatosis, yet its regulation under distinct metabolic contexts remains poorly defined. Here, we identify bile acids (BAs) as critical modulators of hepatic autophagy. Circulating BA levels are elevated in human subjects with liver steatosis and independently associated with increased hepatic steatosis risk. High-fat diet (HFD) feeding increases circulating BA levels, while simultaneously reducing hepatic autophagic flux in mice, whereas pharmacological inhibition of farnesoid X receptor (FXR) enhances autophagy and alleviates steatosis in the livers of HFD-fed mice. Mechanistically, circulating BAs promote hepatic acetyl-CoA production through FXR-induced acyl-CoA oxidase 1 (ACOX1), which in turn suppresses autophagy by increasing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar to HFD feeding, prolonged fasting elevates BA levels and hepatic lipid accumulation, while concurrently upregulating hepatic miR-378, a positive regulator of BA synthesis. Although miR-378 exerts a cell-autonomous pro-autophagic effect during short-term fasting, it paradoxically drives lipid accumulation by suppressing hepatic autophagy via BA/FXR/ACOX1/acetyl-CoA axis in a non-cell-autonomous manner during either HFD feeding or prolonged fasting when BA action becomes considerable. Together, our study uncovers BAs as a previously unrecognized class of inhibitors of hepatic autophagy during prolonged fasting and in metabolic dysfunction-associated steatotic liver disease (MASLD), providing novel insights into context-dependent autophagic regulation of hepatic lipid metabolism and potential therapeutic strategies for MASLD.

Keywords: FXR; autophagy; bile acid; lipid accumulation; miR-378

DOI: https://doi.org/10.1093/lifemeta/loaf038

Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]

Do metabolic fluxes change with age?

Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.

Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.

Keywords: age-associated diseases; aging; autophagy; geroscience; metabolism

DOI: https://doi.org/10.1016/j.tem.2026.01.013

J Hepatol. 2026 Mar 18. pii: S0168-8278(26)00137-6. [Epub ahead of print]

IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration.

Taofei Zeng, Yabin Huang, Hao He, Jiuxiang Chang, Shengwei Tao, Zihao Liu, Rick Francis Thorne, Weiqiao Chen, Kejia Liu, Xuedan Sun, Lianxin Liu, Dalong Yin.

BACKGROUND & AIMS: Liver regeneration is a tightly regulated process requiring coordinated interactions between hepatocytes and non-parenchymal cells; however, its molecular mechanisms remain incompletely defined. Here, we aimed to investigate the role of interferon-related developmental regulator 1 (IFRD1) in regulating metabolic-immune crosstalk during liver regeneration.
METHODS: We integrated public transcriptomic datasets, human liver disease samples, and multiple in-house-generated experimental models to characterize the dynamic expression of IFRD1 during liver regeneration. Genetic loss-of-function approaches, including global and cell type-specific knockout mice, together with adeno-associated virus-mediated gain-of-function strategies, were combined with single-nucleus RNA-seq, ATAC-seq, metabolic and biochemical assays, protein interaction analyses, and in vivo rescue experiments to elucidate the underlying mechanisms and clinical relevance.
RESULTS: Hepatocyte IFRD1 was rapidly induced during the early phase of liver regeneration in mice but markedly diminished in human chronic liver disease. Hepatocyte-specific loss of IFRD1 impaired liver repair and regeneration, whereas IFRD1 overexpression enhanced regenerative responses across multiple models, including partial hepatectomy, toxic liver injury, and hepatic ischemia-reperfusion injury. Mechanistically, IFRD1 was required to sustain hepatocyte β-oxidation and mitochondrial ATP production by stabilizing SLC25A5 through competition with the E3 ubiquitin ligase TRIM21. This ATP boost enables chromatin remodeling in hepatocytes, promoting CCL/CXC chemokine expression to recruit CCR2+ monocytes and expand the regenerative GPNMB+ macrophage pool. Notably, IFRD1 overexpression restored liver regenerative capacity after partial hepatectomy in mice with metabolic dysfunction-associated steatohepatitis or DEN-induced liver fibrosis.
CONCLUSIONS: Our findings define IFRD1 as a key immunometabolic regulator of liver regeneration, mediating hepatocyte metabolic control to macrophage-driven regenerative responses, and support the therapeutic potential of targeting IFRD1 to enhance regenerative capacity in liver disease.
IMPACT AND IMPLICATIONS: Liver regeneration is essential for recovery from surgical resection and acute injury, yet therapeutic options to enhance this process remain limited. Our study identifies the IFRD1-SLC25A5-ATP axis as a critical regulator that coordinates hepatocyte energy metabolism with expansion of pro-regenerative macrophage pool. This previously unrecognized regulatory node provides a scientific rationale for developing therapeutic strategies that enhance IFRD1 function to accelerate liver repair. Although limitations remain, such as undefined upstream regulators of IFRD1, these findings provide a foundation for developing improved therapies for patients with compromised regenerative capacity.

Keywords: APAP; GPNMB; Hepatectomy; Hepatic ischemia–reperfusion injury; Hepatocytes; IFRD1; Lipid associated macrophages; Liver injury; Liver regeneration; Metabolism; Monocyte-Derived Macrophages

DOI: https://doi.org/10.1016/j.jhep.2026.03.012

Cell Metab. 2026 Mar 16. pii: S1550-4131(26)00052-5. [Epub ahead of print]

Metabolic polygenic risk scores for prediction of obesity, type 2 diabetes, and related morbidities.

Obesity and type 2 diabetes (T2D) are metabolic diseases with shared pathophysiology. Traditional polygenic risk scores (PRSs) have focused on these conditions individually, yet the single-disease approach falls short in capturing the full dimension of metabolic dysfunction. We derived a biologically enriched metabolic PRS (MetPRS), a composite score that uses multi-ancestry genome-wide association studies of 20 metabolic traits from over 8.5 million individuals. MetPRS, optimized to predict obesity (O-MetPRS) and T2D (D-MetPRS), outperformed existing PRSs in predicting obesity and T2D across six ancestries. O-MetPRS and D-MetPRS effectively identify individuals at high risk for metabolic multimorbidity and predict clinical outcomes, including GLP-1 receptor agonist initiation. O-MetPRS and D-MetPRS showed an ∼2-fold increased risk of GLP-1 receptor agonist initiation for the top decile versus the middle quintile. The biologically enriched MetPRS has the potential to add an extra layer of information to disease prediction and management approaches for metabolic diseases.

Keywords: GLP-1 receptor agonist; metabolic traits; multi-ancestry GWAS; multimorbidity; obesity; polygenic risk score; type 2 diabetes

DOI: https://doi.org/10.1016/j.cmet.2026.02.009