bims-obesme 2026-06-21 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–06–21
nine papers selected by
Xiong Weng, University of Edinburgh

Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.
Understanding the somatic evolution of metabolic traits.
Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.
Autophagy in adipose tissue thermogenic function.
Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.
Sex-differential associations of MC3R p.F45S with human metabolic profile.
Blood DNA methylation of EIF5A and TGIF1 is associated with adipose tissue health and metabolic outcomes in obesity: a multi-cohort study.
Differentiation of 3T3-L1 Fibroblasts Into Adipocytes.
NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Cell Metab. 2026 Jun 17. pii: S1550-4131(26)00222-6. [Epub ahead of print]

Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.

Jinbao Ye, Qianyi Wan, Xingzhu Liu, Yawen Deng, Zehong Zhang, Haiou Chen, Chaoxin Gao, Shiyu Zhang, Yuedan Zhu, Jinhua Yan, Yu Yuan, Yi Chen, Haiyang Chen.

  The liver is known to play a pivotal role in modulating blood glucose homeostasis through intrahepatic glucose metabolism. Here, we reveal a unique mechanism by which fatty liver exacerbates hyperglycemia through remote communication from hepatocytes to intestinal stem cells (ISCs), independent of enhanced intrahepatic gluconeogenesis. Mechanistically, hepatocyte-derived alkaline phosphatase (ALP) targets α2δ-1 in ISCs to promote the membrane translocation of Cav1.2. This process triggers increased intracellular calcium levels, which subsequently activates the calcineurin/NFATC2 signaling axis, thereby inhibiting SOX21 expression. Then, decreased expression of SOX21 downregulated bone morphogenetic protein 7 (BMP7), ultimately hindering ISCs differentiation into intestinal L-cells. Consequently, the levels of hypoglycemic enteroendocrine hormones secreted by L-cells are decreased, thereby promoting hyperglycemia. Therapeutically, inhibiting ALP synthesis in fatty liver independently reduces blood glucose and synergistically enhances the hypoglycemic effect of metformin. Our study highlights the role of liver-gut communication in regulating the fate of ISC differentiation and blood glucose homeostasis.

Keywords:  SOX21; alkaline phosphatase; blood glucose; fatty liver; intestinal stem cells

DOI:  https://doi.org/10.1016/j.cmet.2026.05.012
Nat Metab. 2026 Jun 16.

Understanding the somatic evolution of metabolic traits.

Radhika Khandelwal, Anand Kumar Sharma.

DOI: https://doi.org/10.1038/s42255-026-01551-7
Cell Death Differ. 2026 Jun 17.

Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation.

Fan Hu, Yafen Ye, Ningning Bai, Jun Xu, Yikai Wang, Yingying Su, Jingjing Sun, Xuhong Lu, Wenfei Li, Rongrong Xu, Tingting Hu, Miriayi Alimujiang, Junfeng Han, Ling Wu, Xiaojing Ma, Ying Yang.

Cellular senescence contributes to obesity-associated adipose dysfunction, yet the upstream regulators of this process remain poorly understood. Here, we identified growth arrest and DNA damage-inducible protein 45 beta (Gadd45b) as an adaptive regulator of adipocyte senescence and systemic metabolic homeostasis. GADD45B expression was elevated in adipose tissue from obese human subjects and positively correlated with senescence-related markers. Adipocyte-specific Gadd45b deletion in mice caused depot-selective remodeling under high-fat diet, with inguinal fat hypertrophy but epididymal white adipose tissue (eWAT) atrophy, accompanied by enhanced DNA damage and pronounced senescence. These alterations thereby contributed to impaired lipolytic response, hepatic steatosis and insulin resistance, underscoring the vital role of Gadd45b in maintaining eWAT expandability during nutritional overload. Mechanistically, Gadd45b deficiency led to hypermethylation of fibroblast growth factor 1b (Fgf1b) promoter and reduced Fgf1 expression in eWAT, thereby exacerbating adipose senescence and metabolic abnormalities, while recombinant FGF1 treatment partially reversed these defects. Collectively, our findings establish Gadd45b as a depot-specific epigenetic regulator that sustains adipose tissue plasticity and links DNA damage responses to adipocyte senescence and metabolic homeostasis in obesity.

DOI: https://doi.org/10.1038/s41418-026-01784-9
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00154-6. [Epub ahead of print]404 197-231

Autophagy in adipose tissue thermogenic function.

Joan Villarroya, Albert Blasco-Roset, Marta Giralt.

  Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, a heat-producing process essential for maintaining body temperature, especially in cold environments. While abundant in newborns, BAT is also present in adults, where it becomes activated under specific stimuli such as cold exposure or food intake. In addition, white adipose tissue (WAT) can undergo a "browning" process, generating beige adipocytes with thermogenic properties similar to classical brown adipocytes. BAT is highly innervated and vascularized, features that support its thermogenic function by facilitating sympathetic nervous system activation and efficient heat distribution. BAT activation increases energy expenditure and plays a protective role against obesity and metabolic disorders. A growing body of evidence highlights autophagy as a critical regulator of BAT and beige adipocyte function. During thermogenic activation, autophagy, especially mitophagy, is suppressed, promoting mitochondrial accumulation and heat production. Conversely, enhanced autophagy contributes to BAT whitening and functional decline, as seen in obesity and aging. Although the role of autophagy in thermogenesis remains unclear, modulating autophagic pathways represents a promising strategy to boost thermogenic activity and improve metabolic health. Understanding the molecular mechanisms underlying BAT plasticity and autophagic regulation could offer novel therapeutic avenues for combating obesity and related metabolic diseases.

Keywords:  adipocyte; aging; autophagy; brown adipose tissue; chaperone-mediated autophagy; thermogenesis

DOI:  https://doi.org/10.1016/bs.ircmb.2025.10.006
Adv Sci (Weinh). 2026 Jun 16. e16501

Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.

Qingwen Zhao, Li Xie, Qianzhuo Wang, Shuying Dai, Bei Li, Yingjuan Zhang, Zhe Sun, Yue Gao.

  Brown and beige adipocytes dissipate energy as heat, yet effective strategies to enhance their mitochondrial efficiency remain limited. Here, we identify Agnuside (AGN) as a selective stabilizer of the complex I assembly factor NDUFAF6. AGN directly binds cytosolic NDUFAF6, suppresses its ubiquitination, prolongs its half-life, and facilitates mitochondrial import, thereby reinforcing complex I assembly and promoting coordinated stabilization of complexes III and IV within the respirasome, without altering complex II, complex V, or global mitochondrial biogenesis. Functionally, AGN exhibits a demand-dependent metabolic profile. Under basal conditions, AGN enhances mitochondrial oxidative efficiency without activating overt UCP1-dependent uncoupling. In contrast, cold exposure or chronic high-fat feeding markedly potentiates its thermogenic impact, as evidenced by improved mitochondrial ultrastructure, increased UCP1 abundance, and elevated energy expenditure in brown adipose tissue, with similar mitochondrial reinforcement observed in inguinal white adipose tissue under sustained metabolic stress. Importantly, thermoneutral Ucp1 knockdown does not abolish AGN-mediated enhancement of respiratory complex assembly and ATP production, whereas genetic ablation of Ndufaf6 eliminates these effects. Together, these findings establish AGN-NDUFAF6 stabilization as a key regulatory mechanism governing adipose mitochondrial efficiency and thermogenic responsiveness, and highlight assembly-factor targeting as a promising strategy to restore oxidative metabolism in metabolic dysfunction.

Keywords:  NDUFAF6; agnuside; brown adipocytes; mitochondria; thermogenesis

DOI:  https://doi.org/10.1002/advs.202516501
J Neuroendocrinol. 2026 Jun;38(6): e70214

Sex-differential associations of MC3R p.F45S with human metabolic profile.

Tanya C Kaur, Andrew R Wood, Gareth Hawkes, Robin N Beaumont, Kartik Chundru, Michael N Weedon, Hugh D Piggins, Kate L J Ellacott.

  Obesity and related metabolic disorders represent major global health challenges, highlighting the importance of understanding the central regulation of energy homeostasis. The melanocortin system is a conserved circuitry governing food intake and other neuroendocrine processes. Within this system, the melanocortin-3 receptor (MC3R) regulates energy and glucose balance, body composition, and linear growth in rodent models, with evidence of sexually dimorphic expression and function. Whether MC3R exerts similar sex-specific effects in humans remains unclear, largely due to the rarity of loss-of-function (LoF) variants. We analysed data from the UK Biobank (UKB), a population-based study comprising 500,000 individuals, to investigate the phenotypic consequences of the rare MC3R LoF variant rs143321797 (p.F45S). Using the largest UKB whole-genome sequencing dataset to date, we performed comprehensive phenotypic analyses, including the first sex-stratified assessment of this variant. Carriage of the MC3R p.F45S variant was associated with differences in adult stature and the timing of sexual maturation. Though the variant was not associated with increased risk of obesity or metabolic disease, carriers exhibited an altered adipose tissue distribution profile characterised by relatively greater subcutaneous fat deposition. Our findings independently validate the role of MC3R in human stature and sexual maturation and identify a previously unreported association with adipose tissue distribution. The absence of increased obesity or metabolic disease risk in MC3R p.F45S carriers of this study, together with a subcutaneous-biased adipose distribution, suggests that MC3R may influence metabolic health through regulation of adipose tissue distribution rather than overall adiposity.

Keywords:  genetic variant; melanocortin; melanocortin‐3 receptor; metabolism; puberty

DOI:  https://doi.org/10.1111/jne.70214
Clin Epigenetics. 2026 Jun 16. pii: 118. [Epub ahead of print]18(1):

Blood DNA methylation of EIF5A and TGIF1 is associated with adipose tissue health and metabolic outcomes in obesity: a multi-cohort study.

Sophie Ruf, Anne Hoffmann, Luise Müller, Kathrin Landgraf, Mandy Vogel, Emil Jørsboe, Phil Kubitz, Arne Dietrich, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Melina Claussnitzer, Hans Hauner, Michael Stumvoll, Ronny Baber, Matthias Blüher, Antje Körner, Peter Kovacs, Maria Keller.

   BACKGROUND: Blood-based DNA methylation has been linked to obesity and metabolic health, yet its relationship to adipose tissue function remains incompletely understood. This study aimed to investigate the epigenetic regulation of EIF5A (Eukaryotic translation initiation factor 5A-1) and TGIF1 (TGFB Induced Factor Homeobox 1) across blood and adipose tissue in obesity.
METHODS: Candidate genes were identified using a multi-step gene selection approach integrating transcriptomic and epigenomic data from blood and adipose tissue samples obtained from children and adults across four diverse population- and disease-focused cohorts. Genes were prioritized based on differential DNA methylation and gene expression in obesity. Targeted bisulfite sequencing of EIF5A and TGIF1 was conducted in blood samples from adults across BMI-defined groups and from children prior to the development of obesity, to validate candidate loci and to examine associations with metabolic and adipocyte-related phenotypes.
RESULTS: In adults from the Leipzig Obesity BioBank, blood DNA methylation (N = 150) of both EIF5A and TGIF1 was significantly increased in individuals with obesity. EIF5A mRNA expression (N = 1554) was significantly higher in omental-visceral adipose tissue compared with subcutaneous adipose tissue. Blood DNA methylation of EIF5A was associated with body mass index (BMI), glycated hemoglobin (HbA1c), and leukocyte counts, particularly among individuals with type 2 diabetes mellitus. In children, blood DNA methylation (N = 75) of EIF5A was associated with longitudinal HbA1c trajectories. For TGIF1, DNA methylation levels were increased in subcutaneous adipose tissue (N = 219) of children with obesity and correlated with fasting serum insulin concentrations. Across cohorts, TGIF1 regulation in both blood and adipose tissue showed consistent associations with adipocyte size. Notably, blood DNA methylation of TGIF1 in childhood was associated with body fat mass and HbA1c at later follow-up despite normal weight at baseline.
CONCLUSION: EIF5A and TGIF1 DNA methylation represent cross-tissue epigenetic signatures linking blood-based DNA methylation to adipose tissue dysfunction, adipocyte hypertrophy, and early metabolic risk. These findings support the potential of blood DNA methylation markers to reflect adipose tissue health and metabolic outcomes across the lifespan.

Keywords:  Adipose tissue; Blood; Childhood; DNA methylation; Epigenetics; Metabolism; Obesity; mRNA expression

DOI:  https://doi.org/10.1186/s13148-026-02177-y
Curr Protoc. 2026 Jun;6(6): e70402

Differentiation of 3T3-L1 Fibroblasts Into Adipocytes.

William J Jones, Rhea Couper, Gwyn W Gould, Nia J Bryant.

  Obesity and type 2 diabetes (T2D) have reached epidemic proportions worldwide, affecting millions of people and contributing to serious health complications, such as metabolic syndrome, cardiovascular disease, and cancer. Adipose tissue is an endocrine organ that serves crucial physiological roles in energy homeostasis. However, excessive adipocyte hypertrophy and altered adipokine profiles underscore metabolic diseases. Understanding the molecular mechanisms governing adipocyte dysfunction is therefore of paramount importance in developing targeted interventions. 3T3-L1 adipocytes have been a cornerstone adipogenic model since their establishment in the 1970s. The enduring popularity of this model is owed to its efficient differentiation capacity, faithful recapitulation of adipogenesis in vivo, and amenability to genetic manipulation. We present detailed protocols for the differentiation and phenotypical assessment of 3T3-L1 adipocytes. We include how to perform lipid-based staining to assess the efficiency of 3T3-L1 differentiation, as well as quantify lipid accumulation per cell. Moreover, we provide step-by-step instructions on performing radiolabeled 2-deoxy-d-glucose uptake in 3T3-L1 adipocytes in response to insulin. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Differentiation of 3T3-L1 fibroblasts into adipocytes Support Protocol 1: Quantification of adipogenic differentiation by Oil Red O staining Support Protocol 2: Quantification of adipogenic differentiation by Nile red and DAPI co-staining Basic Protocol 2: Measurement of radiolabeled glucose uptake in 3T3-L1 adipocytes.

Keywords:  3T3‐L1 differentiation; Oil Red O staining; adipocyte biology; adipocytes; adipogenesis; glucose‐uptake; nile red staining

DOI:  https://doi.org/10.1002/cpz1.70402
Sci Adv. 2026 Jun 19. 12(25): eaec3505

NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.

DOI: https://doi.org/10.1126/sciadv.aec3505