bims-mimead 2026-09-06 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–09–06
five papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
Single-nucleus analysis of human white adipose tissue reveals adipocyte subsets with distinct metabolic profiles.
Androgen-PDH axis modulates sexual dimorphism of mitochondrial respiration in visceral fat.
Adipocyte β3-Adrenergic Receptor Signaling Attenuates Leptin Production but Is Dispensable for Fasting Induced Leptin Suppression.
Additive effects of metformin on glucose homeostasis after metabolic-bariatric surgery in non-obese insulin-deficient diabetic rats.

Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14

Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.

Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.

Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse

DOI:  https://doi.org/10.7554/eLife.106976
Nat Commun. 2026 Aug 05. pii: 9471. [Epub ahead of print]17(1):

Single-nucleus analysis of human white adipose tissue reveals adipocyte subsets with distinct metabolic profiles.

Vissarion Efthymiou, Adhideb Ghosh, Sean D Kodani, Habib Muallem, Xavier Caubit, Waqar Ali, Lindsay S Poulos, Henrique Camara, Anushka Gupta, Yasmine Belaidouni, A Sina Booeshaghi, Shiyi Yang, Ruchir Rastogi, Farnaz Shamsi, Ashley Vernon, Laurent Fasano, Assaf Rudich, Aaron Streets, Yu-Hua Tseng, Mary Elizabeth Patti.

Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis reveals 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAThi vs. ADIPOMATlo). ADIPOMATlo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMATlo were more abundant in higher BMI donors, while SAT-resident ADIPOMATlo associated with impaired glycemia. TSHZ3 is identified as a candidate regulator of ADIPOMATlo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibits differentiation, with downregulation of early adipogenic regulators (e.g., CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduces SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.

DOI: https://doi.org/10.1038/s41467-026-75426-6
Cell Rep. 2026 Sep 03. pii: S2211-1247(26)00972-1. [Epub ahead of print]45(9): 117894

Androgen-PDH axis modulates sexual dimorphism of mitochondrial respiration in visceral fat.

Aibo Gao, Zhiwen Cao, Junlei Su, Bin Gu, Lei Wu, Shaoqian Zhao, Wen Li, Danjie Li, Juan Zhang, Zhongyun Zhang, Minchun Zhang, Muye Tong, Yifei Zhang, Yufang Bi, Guang Ning, Jie Hong, Weiqing Wang, Weiqiong Gu, Jiqiu Wang, Ruixin Liu.

  Sex-dimorphic adipose mitochondrial function (lower activity in males) correlates with visceral adiposity and metabolic risk, yet the underlying mechanisms remain elusive. We find that androgen-androgen receptor (AR) signaling suppresses mitochondrial respiration and thermogenesis in visceral adipose tissue (VAT), promoting visceral fat accumulation. Mechanistically, androgen-AR signaling represses transcription of Pdhb, which encodes a pyruvate dehydrogenase (PDH) subunit, thereby reducing PDH activity, acetyl-CoA levels, H3K27 acetylation, and chromatin accessibility at the promoters of mitochondrial respiration-related genes. Notably, Pdhb overexpression largely reverses these alterations and restores mitochondrial function. Furthermore, sodium dichloroacetate, a PDH activator, enhances mitochondrial respiration and reduces visceral fat in male mice. Multi-omics analyses reveal that the androgen-PDH axis orchestrates a male-specific chromatin-based transcriptional landscape that encompasses mitochondrial and metabolic pathways in visceral adipocytes. Collectively, this study identifies the androgen-PDH axis as a key regulator of sexual dimorphism in mitochondrial metabolism and adipose homeostasis in VAT.

Keywords:  CP: cell biology; CP: metabolism; PDH; Pdhb; acetylation; androgen; mitochondrial respiration; sexual dimorphism; thermogenesis; visceral adipocyte

DOI:  https://doi.org/10.1016/j.celrep.2026.117894
Am J Physiol Endocrinol Metab. 2026 Sep 01.

Adipocyte β3-Adrenergic Receptor Signaling Attenuates Leptin Production but Is Dispensable for Fasting Induced Leptin Suppression.

Samuel R Heaselgrave, Steven C Wyler, Shreya Thomas, Arely Tinajero, Marco Galvan, Emma Mihaila, Roger Fan, Teppei Fujikawa, Philipp E Scherer, Joel K Elmquist.

  Leptin, secreted by adipocytes, conveys the status of peripheral energy stores to the brain to regulate appetite and metabolism. Although sympathetic activation via β3-adrenergic receptors (β3-ARs) has been shown to suppress leptin expression, it remains unclear whether this regulation arises directly within adipocytes or through other populations. Additionally, it is unclear whether β3-AR signaling contributes to the fasting-induced reduction in leptin. To address this, we generated a novel Adrb3 transcriptional block mouse (Adrb3TB/TB) enabling global β3-AR inactivation and adipocyte-specific re- expression (Adrb3TB/TB; Adipoq-Cre). Global loss of Adrb3 increased plasma leptin levels, while re-expression in adipocytes normalized leptin and restored β3-AR agonist-induced leptin suppression. Analysis of Lep mRNA revealed depot specific regulation, with β3-AR signaling predominantly affecting gonadal and subcutaneous white adipose tissue, while brown adipose tissue responses were modest and variable. Despite these effects, fasting for 48 hours comparably reduced plasma leptin and Lep mRNA in both wild-type (WT) and Adrb3TB/TB mice, indicating that β3-AR signaling is not required for the fasting-induced decline in leptin. Collectively, these findings establish adipocyte β3-AR signaling as a key regulator that constrains leptin synthesis under basal and stimulated conditions in male mice, but not during energy deprivation. Together, these findings clarify the role of adipocyte β3-adrenergic signaling in leptin regulation and provide new insight into the sympathetic control of adipose tissue function.

Keywords:  adipocyte; leptin; sympathetic signaling; β3-adrenergic receptor

DOI:  https://doi.org/10.1152/ajpendo.00083.2026
Am J Physiol Endocrinol Metab. 2026 Sep 03.

Additive effects of metformin on glucose homeostasis after metabolic-bariatric surgery in non-obese insulin-deficient diabetic rats.

Mélanie Hirlemann, Mélanie Garmon, Lara Ribeiro-Parenti, Danielle Bailbe, Alexandra Willemetz, Hounayda El-Jindi Shahrour, Jamileh Movassat, Claire Carette, Maude Le Gall.

  This study investigates the individual and combined effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and metformin on glucose regulation in a non-obese, insulin-deficient model of type 2 diabetes. Female Goto-Kakizaki (GK) rats underwent RYGB, SG, or sham surgery. Three weeks postoperatively, animals received metformin (50 mg/kg/day, 5 days/week) or vehicle for three additional weeks. Glucose tolerance was assessed using a standardized meal test, and insulin sensitivity was evaluated by insulin tolerance test. Plasma levels of GLP-1, GIP, insulin, and leptin were measured. RYGB and SG reduced body weight, food intake, and leptin levels, and improved fasting glucose, glucose tolerance, insulin sensitivity, and postprandial incretin and insulin secretion. Metformin alone improved glucose tolerance and insulin sensitivity independently of incretin or insulin changes. When combined with surgery, metformin further reduced postprandial glycemic excursions but did not enhance insulin sensitivity or hormone secretion beyond surgery alone. In conclusion, metabolic-bariatric surgery and metformin independently improve glucose regulation in non-obese diabetic GK rats. Their combination provides additional benefits on postprandial glucose control, despite no additional effects on insulin sensitivity or hormone levels. These findings support the use of metformin as an adjunct to metabolic-bariatric surgery in insulin-deficient diabetes and highlight the need for longer-term, sex-inclusive studies to enhance translational relevance.

Keywords:  Incretin; Metabolic-Bariatric Surgery; Metformin; Type 2 Diabetes

DOI:  https://doi.org/10.1152/ajpendo.00077.2026