bims-mimead 2026-02-15 papers

Issue of 2026–02–15
six papers selected by
Rachel M. Handy, University of Guelph

Mol Metab. 2026 Feb 05. pii: S2212-8778(26)00014-1. [Epub ahead of print] 102330

ANKRD53 is downregulated in human obesity and coordinates lipolysis with mitochondrial oxidative metabolism in adipocytes.

Yingying Su, Xiaoya Li, Yikai Wang, Xuhong Lu, Yafen Ye, Jingjing Sun, Tianwen Liu, Jinghao Cai, Xiaojing Ma, Ying Yang, Jian Zhou.

AIMS: Human adipose tissue is central to obesity-associated metabolic dysfunction. ANKRD53 is a human-specific, adipocyte-enriched ankyrin repeat scaffold protein with largely unknown function. We investigated its role in human adipocyte metabolism and the underlying mechanism.
METHODS: RNA-seq analysis of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 236 individuals quantified ANKRD53 expression and its association with metabolic traits. In human primary adipocytes, we assessed lipolysis (free fatty acid and glycerol release) and mitochondrial respiration (oxygen consumption rate) after ANKRD53 overexpression or knockdown. An AAV was used to overexpress ANKRD53 in mouse inguinal white adipose tissue (iWAT). Protein interactors were identified by immunoprecipitation-mass spectrometry, and knockdown experiments confirmed a functional role of ACSL1.
RESULTS: ANKRD53 expression in both adipose depots was markedly reduced in obesity and inversely correlated with BMI, adiposity measures, insulin resistance indices, and circulating triglycerides, while positively associated with adiponectin and HDL. In human adipocytes, ANKRD53 overexpression enhanced forskolin-stimulated lipolysis and mitochondrial respiration, whereas silencing impaired these processes. Adipose-targeted ANKRD53 overexpression in mice increased lipolysis in vivo. Mechanistically, ANKRD53 interacted with ACSL1 and promoted its mitochondrial localization, channeling lipolysis-derived FFAs into β-oxidation; silencing ACSL1 abrogated ANKRD53's effects.
CONCLUSIONS: ANKRD53 is reduced in obesity and coordinates lipolysis with mitochondrial oxidative metabolism in human adipocytes, promoting efficient use of lipolysis-derived FFAs via ACSL1. These findings establish ANKRD53 as a key regulator of adipocyte energy metabolism and a potential therapeutic target for improving metabolic health in obesity.

Keywords: ACSL1; ANKRD53; Human primary adipocytes; Lipolysis; Mitochondrial oxidative metabolism; Obesity

DOI: https://doi.org/10.1016/j.molmet.2026.102330

Geroscience. 2026 Feb 11.

Low-dose tamoxifen ameliorates ovariectomy-induced metabolic and immune dysfunction.

Heather E McClurg, Amanda Ferraro, Gina Pham, Itzel Morales-Hernandez, Estefania Valencia-Rincon, Kevin D Pham, Willard M Freeman, Jacquelyn A Gorman, Marisol Castillo-Castrejon.

The decline in estrogen following menopause is a major driver of metabolic and immune dysfunction in aging females. While hormone replacement therapy improves many of these outcomes, its clinical use remains limited due to concerns regarding estrogen-sensitive malignancies. Tissue-selective estrogen complexes (TSECs), which combine estrogens with selective estrogen receptor modulators (SERMs) such as tamoxifen (TAM), represent a promising strategy to preserve the metabolic and immunological benefits of estrogen while reducing oncogenic risk. However, the systemic effects of TAM under conditions of estrogen deficiency remain incompletely defined. In this study, we investigated the metabolic and immunomodulatory actions of low-dose TAM, alone or in combination with 17β-estradiol (E2), in adult ovariectomized (OVX) female mice. OVX resulted in increased adiposity, hepatic steatosis, glucose intolerance, insulin resistance, immunoglobulin G3 (IgG3) concentration, and systemic inflammation, along with decreased immunoglobulin G1 (IgG1) concentration. E2, TAM, and E2 + TAM each attenuated OVX-induced adipose expansion, adipocyte hypertrophy, and proinflammatory cytokine production. TAM improved insulin sensitivity but did not fully restore glucose tolerance. Transcriptomic analysis of visceral adipose tissue-resident B cells revealed that E2 and E2 + TAM modulate overlapping yet distinct immune-regulatory networks, including suppression of pro-inflammatory signaling, regulation of immune checkpoints, and genes linked to adipose homeostasis. Low-dose TAM emerges as a modulator of estrogen receptor signaling that attenuates multiple features of OVX-induced metabolic and inflammatory dysfunction, though its limited effect on glycemic control highlights the need for tissue-specific evaluation of SERM-based interventions. These findings provide mechanistic insight into endocrine-immune-metabolic interactions and inform strategies to reduce aging-related disease risk in postmenopausal women.

Keywords: Adipose tissue; B cells; Estrogen; Inflammation; Menopause

DOI: https://doi.org/10.1007/s11357-025-02086-7

Metabolism. 2026 Feb 06. pii: S0026-0495(26)00057-0. [Epub ahead of print]178 156548

Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice.

Jisun So, Jamie Wann, Kyungchan Kim, Solaema Taleb, Hyeong-Geug Kim, Manju Kumari, Alexander S Banks, X Charlie Dong, Hyun Cheol Roh.

BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing this adaptive growth remain incompletely characterized.
METHODS: Super-enhancer landscapes in adipocytes were mapped via H3K27ac chromatin immunoprecipitation sequencing analysis of adipocyte nuclei from mice fed either a standard chow diet or high-fat diet (HFD) to identify transcriptional regulators activated under obesogenic conditions. Functional validation was conducted through both in vitro and in vivo experiments, including adipocyte-specific gene deletion mouse models, followed by single-nucleus RNA sequencing.
RESULTS: Super-enhancer profiling identified Serum Response Factor (SRF) as a critical driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was shown to be both necessary and sufficient for regulation of actin cytoskeletal gene expression in 3T3-L1 adipocytes. Adipocyte-specific SRF ablation in mice led to reduced expression of actin cytoskeletal genes, disruption of actin filament organization, and impaired adipocyte enlargement under HFD feeding. Despite comparable body weight, SRF-deficient mice developed exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, indicative of compromised lipid storage within adipocytes. Single-nucleus RNA-seq further revealed that cell-intrinsic actin cytoskeletal defects in adipocytes propagated to tissue-level dysfunction, impairing vascularization and increasing inflammation.
CONCLUSION: These findings establish SRF as a central regulator of actin cytoskeletal organization that promotes healthy adipocyte hypertrophy and adipose tissue remodeling. Enhancing SRF-dependent cytoskeletal remodeling in adipocytes may offer a therapeutic strategy to preserve metabolic health in obesity.

Keywords: Actin cytoskeleton; Adipocyte hypertrophy; Obesity; Serum Response Factor (SRF); Single-nucleus RNA sequencing; Super-enhancer; Tissue remodeling

DOI: https://doi.org/10.1016/j.metabol.2026.156548

JCI Insight. 2026 Feb 10. pii: e193837. [Epub ahead of print]

CD9 regulates macrophage-mediated remodeling of adipose tissue in obesity.

Julia Chini, Nicole DeMarco, Dana V Mitchell, Sam J McCright, Kaitlyn M Shen, Divyansi Pandey, Rachel L Clement, Jessica Miller, Rajan Jain, Deanne M Taylor, Mitchell A Lazar, David A Hill.

Dysfunctional white adipose tissue contributes to the development of obesity-related morbidities, including insulin resistance, dyslipidemia, and other metabolic disorders. Adipose tissue macrophages (ATMs) accumulate in obesity and play both beneficial and harmful roles in the maintenance of adipose tissue homeostasis and function. Despite their importance, the molecules and mechanisms that regulate these diverse functions are not well understood. Lipid-associated macrophages (LAMs), the dominant subset of obesity-associated ATMs, accumulate in crown-like structures and are characterized by a metabolically activated and proinflammatory phenotype. We previously identified CD9 as a surface marker of LAMs. However, the contribution of CD9 to the activation and function of LAMs during obesity is unknown. Using a myeloid-specific CD9 knockout model, we show that CD9 supports ATM-adipocyte adhesion and crown-like structure formation. Furthermore, CD9 promotes the expression of pro-fibrotic and extracellular matrix remodeling genes. Loss of myeloid CD9 reduces adipose tissue fibrosis, increases visceral adipose tissue accumulation, and improves global metabolic outcomes during diet-induced obesity. These results identify CD9 as a causal regulator of pathogenic LAM functions, highlighting CD9 as a potential therapeutic target for treating obesity-associated metabolic disease.

Keywords: Adipose tissue; Immunology; Macrophages; Metabolism

DOI: https://doi.org/10.1172/jci.insight.193837

Am J Physiol Endocrinol Metab. 2026 Feb 11.

Changes in weight and metabolic health during and after cessation of a time-restricted feeding plus aerobic training in Swiss mice fed a high-fat diet.

Renan Fudoli Lins Vieira, Susana Castelo Branco Ramos Nakandakari, Gabriel Calheiros Antunes, Ana Paula Azevedo Macedo, Robson Damasceno de Lima, Thaiane da Silva Rios, Natalia Tobar, Vitor Rosetto Muñoz, Rafael Calais Gaspar, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Eduardo Rochete Ropelle, Amandine Chaix, José Rodrigo Pauli.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with high-fat diet (HFD) during an 8-week intervention of TRF (8 h food access in the active phase) or TRF combined with EXE (60 min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest BW and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations.These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.

Keywords: Exercise; Intermittent Fasting; Obesity; Time-Restricted Eating; Weight Gain

DOI: https://doi.org/10.1152/ajpendo.00432.2025

Diabetologia. 2026 Feb 13.

Novel deuterium metabolic imaging technique reveals distinct patterns of postprandial hepatic glucose homeostasis in individuals with type 1 diabetes and healthy control individuals: a case-control study.

Alessandro Brunasso, Naomi F Lange, Simone Poli, Michele Schiavon, David Herzig, Chiara Dalla Man, Roland Kreis, Lia Bally.

AIMS/HYPOTHESIS: Subcutaneous insulin delivery in individuals with insulin-deficient type 1 diabetes bypasses the portal circulation, disrupting the physiological porto-systemic insulin gradient and affecting postprandial hepatic glucose regulation. However, direct, non-invasive measurement of these liver-specific dynamics and their deviation from normal physiology in individuals with type 1 diabetes is challenging. To address this, we integrated metabolic imaging with whole-body tracer dilution to map postprandial glucose metabolism in both the liver and systemically in adults with type 1 diabetes and healthy control individuals.
METHODS: In this cross-sectional study, ten adults with type 1 diabetes and ten healthy control individuals with similar age, BMI and gender distributions were enrolled. After an overnight fast, participants ingested 60 g [6,6'-2H2]-glucose (D-Glc); subcutaneous insulin was administered to type 1 diabetes participants according to their carbohydrate-to-insulin ratio. Interleaved deuterium metabolic imaging (DMI) and 13C-magnetic resonance spectroscopy (13C-MRS) at 7 T were performed from pre-ingestion to 150 min post-ingestion to quantify hepatic D-Glc and glycogen concentrations. Blood samples were collected to measure plasma glucose, insulin and glucagon. Postprandial glucose-insulin dynamics were quantified using the single tracer oral minimal model, accounting for non-steady-state insulin exposure.
RESULTS: At baseline, individuals with type 1 diabetes had significantly higher plasma glucose concentrations than control individuals (10.7±2.3 and 5.2±0.4 mmol/l, respectively; p<0.001), while preprandial glycogen levels did not differ significantly. Following D-Glc administration, hepatic D-Glc increased more markedly in the individuals with type 1 diabetes compared with the control group (peak values 4.7±2.0 and 3.0±0.8 mmol/l, respectively; p=0.02). In the postprandial period, glycogen levels did not significantly rise at 150 min in type 1 diabetes, whereas a clear increase was observed in control individuals (iAUC0-180=2.4 mol/l × min). Despite similar systemic insulin exposure and no significant differences in postprandial glucagon concentrations between groups, individuals with type 1 diabetes demonstrated significantly reduced suppression of endogenous glucose production (p=0.001) but similar insulin-dependent glucose disposal. Hierarchical clustering identified two distinct type 1 diabetes subgroups: Subgroup 1 exhibited a steeper increase in both hepatic and systemic D-Glc profiles, while subgroup 2 showed a divergent D-Glc trajectory and net glycogen depletion relative to accumulation in subgroup 1 (iAUC0-180=-3.0 vs 2.5 mol/l × min, p=0.04), despite no overt clinical differences between subgroups.
CONCLUSIONS/INTERPRETATION: By integrating DMI/13C-MRS liver imaging with systemic stable-isotope modelling, this comparative study demonstrates significantly altered hepatic glucose metabolism in adults with well-managed type 1 diabetes vs control individuals, together with substantial phenotypic heterogeneity within the type 1 diabetes cohort. These findings highlight the potential of non-invasive metabolic phenotyping to resolve metabolic alterations and inter-individual variation in type 1 diabetes, which are essential steps towards the provision of precision medicine.

Keywords: Deuterium metabolic imaging; Endogenous glucose production; Glucose fluxes; Glucose metabolism; Glycogen; Insulin sensitivity; Liver glucose metabolism; Magnetic resonance spectroscopy; Stable isotopes; Type 1 diabetes

DOI: https://doi.org/10.1007/s00125-026-06677-7