bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–07–05
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. SETD7 depletion enhances white adipose browning and ameliorates metabolic disorders in obese mice.
  2. TRPC6 loss triggers mitochondrial dysfunction that drives white adipose tissue vulnerability to obesity and insulin resistance.
  3. Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.
  4. A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.
  5. Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.
  6. Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.
  7. The interplay between the microbiome and immune cells in metabolic homeostasis and disease.
  8. Zonated mechanosensing by PIEZO1 controls liver regeneration.
  9. Convergence of metabolic risk in obesity and normal BMI: does risk disappear?
  10. DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
  11. Mitochondrial quality control in human ageing and longevity.
  12. Associations of proteomic age clocks with lifestyle risk factors, incident chronic diseases and mortality in two European cohorts.
  13. Rare protein-coding variation and the genetic architecture of height in >1.4 million individuals.
  1. Cell Death Differ. 2026 Jul 01.
    SETD7 depletion enhances white adipose browning and ameliorates metabolic disorders in obese mice.
    Chenxi Xiao, Yajie Hu, Jiayao Liu, Jialin Zhao, Jie Xu, Honghong Chen, Qiuyuan Huang, Wugui Chen, Jun Chang, Xinhua Liu, Chengshou Lin.
      Obesity, a major global health challenge associated with metabolic and cardiovascular disorders, has drawn increasing attention to the therapeutic potential of white adipose tissue (WAT) browning. Although the lysine methyltransferase SETD7 has been implicated in various cardiovascular and metabolic diseases, its role in adipose thermogenesis remains unclear. Here, we reported that SETD7 was upregulated in inguinal WAT (iWAT) of obese mice and was primarily localized to mature adipocytes. Setd7 knockdown (Setd7⁺/⁻) mice exhibited enhanced thermogenic gene expression and iWAT browning upon cold exposure or β3-adrenergic stimulation, whereas thermogenic activity in brown adipose tissue (BAT) remained largely unaffected. In vitro, SETD7 knockdown did not alter adipogenesis but potently augmented thermogenic capacity in beige adipocytes, while SETD7 overexpression exerted the opposite effect. Mechanistically, RNA-Seq analysis revealed that SETD7 deficiency upregulated Adcy7 transcription, leading to increased Sirt1 levels and enhanced Creb1 phosphorylation, thereby activating the thermogenic program. Notably, Setd7⁺/- mice resisted high-fat diet (HFD)-induced obesity, exhibiting reduced weight gain, elevated energy expenditure, and improved metabolic health. Together, these findings identify SETD7 as a negative regulator of iWAT thermogenesis and suggest that targeting SETD7 may represent a promising strategy for combating obesity.
    DOI:  https://doi.org/10.1038/s41418-026-01790-x
  2. Exp Mol Med. 2026 Jul 03.
    TRPC6 loss triggers mitochondrial dysfunction that drives white adipose tissue vulnerability to obesity and insulin resistance.
    Phan Anh Nguyen, Kyu-Hee Hwang, Duyen Thi Thuy Tran, Tae Sic Lee, Kyu-Sang Park, Seung-Kuy Cha.
      Calcium signaling is essential for adipocyte function; however, the upstream Ca2+ channels coordinating adipose metabolism remain poorly defined. Here, we identify TRPC6 as a Ca2+ channel enriched in early adipocyte progenitors that orchestrate white adipose tissue (WAT) homeostasis by integrating cAMP signaling and mitochondrial bioenergetics. In Trpc6 knockout mice, WAT emerges as the earliest and most vulnerable site of dysfunction, exhibiting pathological hypertrophic lipid accumulation despite impaired adipogenesis and intact hypothalamic signaling. Mechanistically, TRPC6 deficiency disrupts cAMP-hormone-sensitive lipase signaling and impairs mitochondrial oxidative metabolism, processes sustained by a reciprocal TRPC6-cAMP feedback loop. TRPC6 is transiently expressed during early adipogenic commitment and is indispensable for proper progenitor differentiation and lipid turnover. These findings define TRPC6 as a molecular gatekeeper that links Ca2+ and cAMP signaling to mitochondrial metabolism, ensuring adipocyte plasticity and energy balance. Moreover, our study reveals a previously unrecognized mechanism that underlies WAT vulnerability to metabolic dysfunction and highlights the therapeutic potential of the TRPC6-cAMP-mitochondrial axis in obesity and insulin resistance.
    DOI:  https://doi.org/10.1038/s12276-026-01775-3
  3. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2524943123
    Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.
    Biyi Chen, Jinxi Wang, Qingwen Qian, Guangqin Zhang, Yihui Wang, Mark Li, Rubin Tan, Zhuoying Yang, Weiyang Zhao, Grace Ciampa, Daniela Sarahi Yang Bennett, Yixi Liu, Qi Zhu, Zhiyong Zhu, Sepiso K Masenga, Zer Vue, Han Le, Qian Shi, Leonid V Zingman, Antentor O Hinton, Duane D Hall, E Dale Abel, Ling Yang, Long-Sheng Song.
      Dysfunctional adipocyte calcium handling is implicated in obesity and thermogenesis. Junctophilins (JPs) stabilize calcium microdomain junctions between the plasma membrane and endoplasmic reticulum, but whether JPs are required for adipocyte function is not known. We show that JP2 is enriched in thermogenic brown adipose tissue (BAT) relative to other fat depots and is downregulated under conditions of nutrient overload. Conditional knockdown of JP2 in adipocytes, and more selectively in BAT, exacerbates cold intolerance and susceptibility to diet induced obesity. Mechanistically, JP2-depleted brown adipocytes exhibit calcium handling dysfunction with elevated cytosolic calcium levels at baseline but diminished norepinephrine-induced calcium transients, reduced store-operated calcium entry. Basal cytosolic calcium overload accounts for an increase in calpain activation and ensuing downregulation of STIM1 and hormone-sensitive lipase in JP2-depleted cells. Furthermore, JP2 silencing in brown adipocytes reduced oxygen consumption rates and compromised mitochondrial structure and quality. Together, these findings demonstrate that JP2 is essential for normal calcium homeostasis in brown adipocytes and reveal a critical role for JP2 in thermogenesis and resistance to diet-induced metabolic dysregulation.
    Keywords:  Junctophilin-2; brown adipose tissue; calcium regulation; metabolism; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2524943123
  4. Metabolism. 2026 Jul 01. pii: S0026-0495(26)00196-4. [Epub ahead of print]183 156685
    A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.
    Seongjun Byun, Chan Hyeong Lee, Kyumin Jang, Minwoo Pak, Hyun-Ji Lee, Seongryeol Ryu, Inkyung Jung, Jungeun An, Myunggon Ko.
      Adipose tissue thermogenesis is a major determinant of energy homeostasis, and its dysregulation contributes to obesity and metabolic disease. Parkin-mediated mitophagy is required for thermogenic adaptation, but the upstream mechanisms linking thermal cues to this pathway remain poorly defined. Here, we identify the ten-eleven translocation (TET) family of DNA dioxygenases as thermosensitive epigenetic regulators of Prkn transcription in adipocytes. Cold exposure coordinately suppressed TET expression and reduced global 5-hydroxymethylcytosine (5hmC) levels in white and brown adipose tissue through β-adrenergic signaling. Adipose-specific TET triple-knockout mice exhibited enhanced white fat beiging, brown fat activation, increased energy expenditure, and improved cold tolerance. Transcriptomic network analysis identified Parkin as a key mitophagy node in TET-deficient adipose tissue. Consistent with this, loss of adipose TET reduced Parkin expression, impaired mitophagic flux, and promoted accumulation of metabolically active mitochondria with increased respiratory capacity. Mechanistically, TET proteins occupied the Prkn promoter and maintained a transcriptionally permissive state through catalytic conversion of 5-methylcytosine to 5hmC, whereas TET loss increased promoter methylation and suppressed Prkn expression. Re-expression of wild-type, but not catalytically inactive, Parkin largely normalized mitochondrial content and respiratory activity in TET-deficient adipocytes. Together, these findings define a thermosensitive TET-Parkin epigenetic axis that links environmental cold signals to mitochondrial quality control during adaptive thermogenesis.
    Keywords:  Adaptive thermogenesis; Adipose tissue browning; Epigenetic regulation; Mitophagy; Parkin; TET dioxygenase
    DOI:  https://doi.org/10.1016/j.metabol.2026.156685
  5. EMBO J. 2026 Jul 03.
    Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.
    Rebeca Acin-Perez, Essam A Assali, Michaela Veliova, Jennifer Ngo, Alexandra J Brownstein, Francisco Villalobos, Anton Petcherski, Pablo Hernansanz-Agustin, Doyeon Kim-Vasquez, Shili Xu, Mikayla Tamboline, Raquel Maria Silva, Alexander Upcher, Cynthia Shu, Daniel E Ferriss, Marc Liesa, Jose Antonio Enriquez, Israel Sekler, Orian S Shirihai.
      Adrenergic stimulation of brown adipocytes induces a robust detachment of mitochondria from lipid droplets (LD), which is followed by lipolysis and lipid catabolism. However, the signals inducing mitochondria attachment or detachment, and their role in lipid metabolism, remain unknown. Here, we reconstituted mitochondria-LD interaction in brown adipocyte tissue (BAT) ex vivo. We find that removal of mitochondria from lipid droplets permits higher lipolytic activity of recombinant lipases. Testing the effect of thermogenic secondary messengers and metabolites on attachment and detachment identified elevated mitochondrial matrix calcium as a potent inducer of detachment. Further, deletion of the mitochondrial sodium/calcium exchanger, NCLX, resulted in reduced attachment and increased detachment, while activation of NCLX increased attachment. We find that elevated matrix calcium causes detachment by inducing architectural transformation of peridroplet mitochondria (PDM) from their typical LD-surface-bound crescent shape into a round shape. PDE2A inhibition activates NCLX and increases PDM content in BAT in vitro and in vivo. We conclude that a surge in mitochondrial matrix calcium ions serves as a potent signal to induce mitochondrial detachment from lipid droplets, thereby facilitating lipolysis.
    DOI:  https://doi.org/10.1038/s44318-026-00827-8
  6. Metabolism. 2026 Jun 30. pii: S0026-0495(26)00197-6. [Epub ahead of print] 156686
    Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.
    Zi-Qi Xu, Xin-Yi Yu, Jin-Qiu Wei, Qian-Wan Deng, Wen-Hui Zhai, Wu-Wei Rong, Meng-Yao Li, Qi-Rong Zhang, Ping-Jin Gao, Xiao-Dong Li, Ji-Guang Wang.
      Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide receptor C (NPRC) as a key regulator of insulin transport and insulin sensitivity. NPR-C expression was increased in endothelial cells from adipose tissue and skeletal muscle of obese mice. Endothelial-specific deletion of NPR-C improved insulin sensitivity, whereas endothelial NPR-C overexpression aggravated insulin resistance, as demonstrated by glucose tolerance, insulin tolerance, and hyperinsulinemic-euglycemic clamp. Mechanistically, NPR-C impaired insulin uptake and transendothelial transport by reducing insulin receptor (IR) membrane localization and altering intracellular trafficking. NPR-C directly interacted with Caveolin-1 and promoted Tyr14 phosphorylation-dependent K48-linked ubiquitination and proteasomal degradation of Caveolin-1, disrupting caveolae function and impairing IR trafficking. Importantly, Cdh5 promoter-driven adeno-associated virus-mediated NPR-C knockdown improved insulin sensitivity in mice with established obesity. Together, these findings identify endothelial NPR-C as a regulator of Caveolin-1 stability and IR trafficking and suggest NPR-C as a potential therapeutic target for obesity-associated insulin resistance.
    DOI:  https://doi.org/10.1016/j.metabol.2026.156686
  7. Cell Metab. 2026 Jun 29. pii: S1550-4131(26)00230-5. [Epub ahead of print]
    The interplay between the microbiome and immune cells in metabolic homeostasis and disease.
    Hagit Shapiro, Birgit Jickeli, Idan Niv, Ben Ernan, Eran Elinav.
      Microbiome-derived metabolites, including short-chain fatty acids, bile acids, indoles, and lipopolysaccharides, among other bioactives, modulate mammalian immune cells through a variety of molecular processes, including epigenetic remodeling, mitochondrial metabolic reprogramming, and regulation of mTOR and AMPK signaling pathways. These diverse signals shape inflammatory programs that influence metabolic outcomes in a context-dependent manner, which may sustain metabolic health or drive chronic inflammation impacting obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. Here, we review these metabolite-driven immune-metabolic influences and highlight innovative directions in their exploration, including integration of spatial and single-cell multi-omics to deconvolute microbiome-derived signaling networks within metabolic tissues. We further outline emerging microbiome-based therapeutic strategies targeting immune pathways in cardiometabolic disease, ranging from personalized nutrition, precision probiotics, and microbial consortium transplantation to metabolite-based postbiotics. Collectively, advancing our understanding of host immune-microbiome-metabolic interactions may support the development of targeted interventions for the prevention and treatment of cardiometabolic diseases.
    Keywords:  immune system; metabolism; metabolites; microbiome; microbiota; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.004
  8. Science. 2026 Jul 02. 393(6806): eaef0825
    Zonated mechanosensing by PIEZO1 controls liver regeneration.
    Ying Zhang, Yuzhuo Sun, Guangkui Xu, Yue Wu, Zhijun Shi, Zhuo Chang, Junjun Liu, Kaidan Pang, Siyu Liu, Han Wang, Weixin Rong, Zehua Shao, Xingqian Liu, Yu He, Yang Yan, Bin Zhou, Zuyi Yuan, Xu-Feng Zhang, Stefan Offermanns, Shengpeng Wang.
      The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4+ hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4+ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.
    DOI:  https://doi.org/10.1126/science.aef0825
  9. Lancet. 2026 Jul 01. pii: S0140-6736(26)01245-6. [Epub ahead of print]
    Convergence of metabolic risk in obesity and normal BMI: does risk disappear?
    Yuan Lu.
      
    DOI:  https://doi.org/10.1016/S0140-6736(26)01245-6
  10. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00075-9. [Epub ahead of print]91 102185
    DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
    Melissa Geng, Dahai Wang, Sam Kavoosi, Brett A Kaufman, Neal Sondheimer.
      Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.
    Keywords:  Autophagy; Guanine quadruplex; Heteroplasmy shifting; Mitochondrial fission; Mitochondrial heteroplasmy
    DOI:  https://doi.org/10.1016/j.mito.2026.102185
  11. Nat Metab. 2026 Jun 29.
    Mitochondrial quality control in human ageing and longevity.
    Anna Picca, Luigi Ferrucci.
      Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.
    DOI:  https://doi.org/10.1038/s42255-026-01563-3
  12. Nat Aging. 2026 Jun 29.
    Associations of proteomic age clocks with lifestyle risk factors, incident chronic diseases and mortality in two European cohorts.
    Oliver Robinson, Han Xiao, Jan Homann, Vivian Viallon, Pietro Ferrari, Philipp Frank, José M Huerta, Ana Jiménez Zabala, Rudolf Kaaks, Verena A Katzke, Mika Kivimaki, Claudia Langenberg, Chung-Ho E Lau, Lefkos Middleton, N Charlotte Onland-Moret, Salvatore Panico, Anna Prizment, Fulvio Ricceri, María-José Sánchez, Karl Smith-Byrne, W M Monique Verschuren, Roel Vermeulen, Paolo Vineis, Shuo Wang, Nick Wareham, Christina M Lill, Elio Riboli, Marc J Gunter.
      Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study. We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.
    DOI:  https://doi.org/10.1038/s43587-026-01163-6
  13. medRxiv. 2026 Jun 24. pii: 2026.06.22.26355163. [Epub ahead of print]
    Rare protein-coding variation and the genetic architecture of height in >1.4 million individuals.
    BELIEVE Study Group
      Highly heritable, polygenic, and easily measured, adult height has long been the model trait in human genetics 1,2 . While the landscape of height-associated common genetic variation has been studied extensively 2 , rare variation remains relatively unexplored 1 . Using rare protein-altering variants in a discovery set of 826,066 exomes, we identify 207 height-associated genes - 98% of which replicate in an additional 624,567 individuals. The rarest and most deleterious class of variation, singleton (frequency <0.0001%) putative loss-of-function (pLoF) variants implicated 17 genes with large effects on height ranging from -17 cm ( ACAN ) to +11 cm ( FBN1 ) per allele, 52× larger than the average effect of common height-associated variants and comparable to the 1% tails of a common variant polygenic score. Several genes (e.g., TET1 , DTL , IGF2BP2 ) have effect sizes at least as large as established Mendelian height genes but lack documented stature or skeletal growth syndromes. This is particularly true for genes in which rare variants associate with increased height. We performed the largest rare-variant study of height to date, directly implicate 207 genes that broadly overlap with both GWAS associations and Mendelian height syndromes, assess the impact of rare variants on heritability and prediction, provide evidence that height is an underappreciated clinical feature of Mendelian disorders, and demonstrate the utility of large population-scale sequencing studies for classifying individual variants and dissecting complex trait architecture.
    DOI:  https://doi.org/10.64898/2026.06.22.26355163
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