bims-mimead 2025-12-14 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–12–14
seven papers selected by
Rachel M. Handy, University of Guelph

Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.
Adipose tissue-derived microRNAs as epigenetic modulators of type 2 diabetes.
Inhibition of adipocyte lipolysis by vaspin impairs thermoregulation in vivo.
Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator.
miR-494 Deletion Improves Glucose Metabolism Independently of Obesity in Mice.
GLP-1 from the distal gut is dispensable for body weight and glucose regulation but slows small intestinal transit in female mice.
Editing DNA methylation in vivo.

Aging Cell. 2025 Dec 10. e70318

Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.

Chung-Yang Yeh, Alexis L Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.

  Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.

Keywords:  BHB; caloric restriction; dietary restriction; ketogenesis; ketones; metabolic health; metabolism

DOI:  https://doi.org/10.1111/acel.70318
BMC Med. 2025 Dec 09. 23(1): 678

Adipose tissue-derived microRNAs as epigenetic modulators of type 2 diabetes.

Ratika Sehgal, Neele Haacke, Alice Maguolo, Fiorella A Solari, Markus Jähnert, Pascal Gottmann, Emma Nilsson, Allan Vaag, Pamela Fischer-Posovszky, Anja Werberger, Andreas L Birkenfeld, Andreas Fritsche, Hans-Ulrich Häring, Albert Sickmann, Heike Vogel, Charlotte Ling, Meriem Ouni, Annette Schürmann.

   BACKGROUND: White adipose tissue (WAT) dysfunction including an aberrant expression of miRNAs is strongly associated with the risk of developing type 2 diabetes (T2D), with limited evidence linking early changes in the WAT-derived miRNAs and T2D. The present study aims to identify early miRNome changes prognostic for T2D in mice and humans.
METHODS: Gonadal (g) WAT of diabetes-resistant and diabetes-prone mice were subjected to multi-omics analyses (transcriptome, miRNome, methylome, proteome). Metabolic phenotypes linked with T2D were correlated with adipose tissue miRNA expression and DNA methylation from 14 monozygotic twin pairs discordant for T2D. Plasma miRNA levels from females at high risk of developing T2D (TÜF study) were included.
RESULTS: Adipose tissue of the diabetes-susceptible mice was less insulin sensitive with ~ 200 differentially expressed mature miRNAs compared to diabetes-resistant mice. Integrative analysis of miRNome-transcriptome-proteome identified 227 proteins involved in amino acid metabolism, inflammation, signalling pathways, and insulin resistance. More than 20 differentially expressed miRNAs are located in the imprinted region Dlk1-Gtl2 and Mest (miR-335) potentially regulated by DNA methylation. Imprinted miRNAs also exhibited similar alterations in adipose tissue from monozygotic twin pairs discordant for T2D, with miR-335 expression altered only in females. Moreover, plasma levels of miR-335-5p were negatively correlated with fasting blood glucose in females at high risk of developing T2D.
CONCLUSIONS: Early alterations of WAT-derived miRNAs such as miR-335-5p could contribute to systemic metabolic changes associated with the risk of developing T2D.

Keywords:  Adipose tissue; Discordant monozygotic twins; Epigenetics; Imprinting; MicroRNA (miRNA); Multiomics; New Zealand Obese (NZO) mice; Type 2 diabetes (T2D)

DOI:  https://doi.org/10.1186/s12916-025-04560-7
Nat Commun. 2025 Dec 10. 16(1): 11075

Inhibition of adipocyte lipolysis by vaspin impairs thermoregulation in vivo.

Inka Rapöhn, Helen Broghammer, Anne Hoffmann, Kevin Möhlis, Anna Moormann, Isabell Kaczmarek, Doreen Thor, Henning Großkopf, Laura Krieg, Isabel Karkossa, Kristin Schubert, Martin von Bergen, Kerstin Krause, Jana Breitfeld, Peter Kovacs, Nora Klöting, Rima Nuwayhid, Stefan Langer, Adhideb Ghosh, Christian Wolfrum, Michael Stumvoll, Matthias Blüher, John T Heiker, Juliane Weiner.

Altered activity of brown adipose tissue (BAT) contributes to obesity, insulin resistance, and cardiovascular disease. BAT secretes endocrine factors ("batokines") that regulate thermogenesis. We identify the serpin vaspin as a batokine that modulates adrenergic control of lipolysis and thermogenesis. Adipocyte-specific vaspin overexpression in mice reduces BAT activation and impairs thermoregulation during cold exposure or fasting. Mechanistically, vaspin binds low-density lipoprotein receptors (LRP1, LDLR, vLDLR), inhibiting adrenergic signaling and lipolysis in brown and white adipocytes by modulating phosphodiesterase activity and endocytic lipid uptake. Gene set enrichment analyses in human subcutaneous adipose tissue and in vitro studies confirm vaspin's anti-lipolytic effects in humans. Overall, vaspin emerges as a regulatory BATokine that fine-tunes BAT thermogenic activity to limit excessive energy expenditure and preserve metabolic balance.

DOI: https://doi.org/10.1038/s41467-025-66950-y
Diabetologia. 2025 Dec 09.

Empagliflozin improves beta cell function independently of relief of glucotoxicity in patients with type 2 diabetes: results from a randomised cross-over study with insulin as comparator.

Roopameera Thirumathyam, Erik A Richter, Gerrit van Hall, Nicoline R Andersen, Per L Madsen, Jens J Holst, Sten Madsbad, Nils B Jørgensen.

   AIMS/HYPOTHESIS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve beta cell function in individuals with type 2 diabetes. It has been suggested this is due to relief of glucotoxicity, but the mechanism is unknown. The objective of the present study was to evaluate the effect of the SGLT2 inhibitor empagliflozin, compared with NPH insulin treatment, on beta cell function, and, secondarily, on insulin sensitivity.
METHODS: In this open-label, randomised, cross-over study, 17 individuals with non-insulin-treated type 2 diabetes were randomised to receive 5 weeks of treatment with either empagliflozin or insulin titrated to a similar level of glycaemic control as with empagliflozin before crossing over to the other treatment. Key inclusion criteria included age ≥18 years, BMI ≥ 28 kg/m2, and a diabetes duration of more than 3 months. Treatments were preceded by a 3 week washout. Fasting and post-OGTT (5 h) metabolism were studied before and during treatments. Beta cell glucose sensitivity (bGS) was calculated as the slope of the linear relationship between the pre-hepatic insulin secretion rate and the corresponding plasma glucose value, and insulin sensitivity was calculated as glucose clearance relative to insulin concentrations. Endogenous glucose production, tissue glucose disposal and lipolysis were measured using stable isotopes. The disposition index was calculated as bGS × insulin sensitivity to assess beta cell function. Data for the present study were collected at the Department of Endocrinology, Hvidovre Hospital, Denmark.
RESULTS: All participants who completed the study were included in the analyses. With equipoised glycaemic control, insulin concentrations were higher during insulin treatment than during empagliflozin treatment. bGS and insulin sensitivity were higher during empagliflozin treatment than during insulin treatment. The disposition index thus improved during empagliflozin treatment compared with insulin treatment.
CONCLUSIONS/INTERPRETATION: With similar glycaemic control, insulin sensitivity was higher and beta cell function improved during empagliflozin compared with insulin treatment, possibly due to a disinhibitory effect of lower insulin concentrations.
TRIAL REGISTRATION: EudraCT 2017-002101-35.
FUNDING: This study was supported by Boehringer Ingelheim. Additional funding was provided by the Grosserer L.F. Foghts Fond, Charlottenlund, Denmark.

Keywords:  Beta cell function; Glucotoxicity; Hyperinsulinaemia; Insulin; Sodium–glucose co-transporter 2 inhibition; Type 2 diabetes

DOI:  https://doi.org/10.1007/s00125-025-06616-y
Diabetes. 2025 Dec 12. pii: db250355. [Epub ahead of print]

miR-494 Deletion Improves Glucose Metabolism Independently of Obesity in Mice.

Lucia Sugawara, Katsutaro Morino, Hirotaka Iwasaki, Natsuko Ohashi, Shogo Ida, Koichiro Murata, Tsuyoshi Yanagimachi, Itsuko Miyazawa, Mengistu Lemecha, Takeshi Imamura, Satoshi Ugi, Seiya Mizuno, Satoru Takahashi, Yukihiro Fujita, Hiroshi Maegawa, Shinji Kume.

The browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cultured adipocytes via regulation of peroxisome proliferator-activated receptor γ coactivator 1α, and its inhibition is expected to promote browning and thereby improve obesity and metabolic disorders. To assess its in vivo role and therapeutic potential, we generated miR-494-knockout (KO) mice using CRISPR/Cas9. KO mice showed increased browning of WAT and resistance to high-fat diet-induced obesity. Notably, they also exhibited improved glucose tolerance, even under normal chow feeding conditions without weight loss. Ex vivo analysis revealed enhanced β-adrenergic-stimulated oxidative phosphorylation directly induced by miR-494 deletion. Metabolomic and Seahorse analyses further suggested accelerated glucose metabolism independent of insulin secretion or sensitivity. Analysis of human adipose tissue transcriptomic data supported the association between low miR-494 expression and better glucose tolerance without weight differences. These findings suggest that suppression of miR-494 improves glucose metabolism through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight. Targeting miR-494 could represent a potential therapeutic strategy for obesity and various forms of diabetes.
ARTICLE HIGHLIGHTS: Browning of white adipose tissue enhances energy expenditure and may improve metabolic health; however, it remains unclear whether inhibition of its suppressor, miRNA-494 (miR-494), can exert therapeutic effects in vivo. We investigated whether genetic deletion of miR-494 expression in vivo promotes adipocyte browning, exerts antiobesity effects, and improves glucose tolerance. miR-494-knockout mice showed resistance to high-fat diet-induced obesity and improved glucose tolerance, even under normal chow feeding conditions. miR-494 inhibition may offer a therapeutic strategy for improving glycemic control through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight.

DOI: https://doi.org/10.2337/db25-0355
Am J Physiol Endocrinol Metab. 2025 Dec 10.

GLP-1 from the distal gut is dispensable for body weight and glucose regulation but slows small intestinal transit in female mice.

Thomas Uwe Greiner, Randy J Seeley, Fredrik Bäckhed.

  Enteroendocrine cells (EECs) are specialized cells located throughout the gastrointestinal (GI) tract where they have an essential role in regulating various physiological processes related to digestion, metabolism, and gut physiology. EECs secrete different hormones in response to food intake and the presence of nutrients in the gut, which regulate digestion, appetite, insulin secretion, and energy balance. One of the most well-studied hormones is glucagon-like peptide-1 (GLP-1), which is produced by L-cells in both the small intestine and the colon. Colonic GLP-1-secreting L-cells are not immediately exposed to food and are thus less likely to be responsible for the release of GLP-1 that occurs shortly after ingestion of a meal. Here we sought to determine the role of GLP-1 produced from the distal gut, by generating mice with a deletion of the gene encoding proglucagon (Gcg) in the distal gut and analyzed the effects on body weight, glucose metabolism, and gut transit. Deletion of Gcg in the distal gut reduced circulating levels of GLP-1 but did not affect glucose metabolism or insulin levels on a chow diet or body weight gain or glucose metabolism on a Western-style diet. However, we observed that deletion of distal gut GLP-1 resulted in faster small intestinal transit in female but not male mice. We successfully developed a mouse model that can target L-cells in the distal gut and demonstrate that GLP- 1 from the distal gut is dispensable for weight and glucose regulation, while regulates gut motility in female mice.

Keywords:  GLP-1; Metabolism; Transit

DOI:  https://doi.org/10.1152/ajpendo.00158.2025
Nat Commun. 2025 Dec 10.

Editing DNA methylation in vivo.

Richard Pan, Jingwei Ren, Xinyue Chen, Luis F Flores, Rachel V L Gonzalez, Andre Antonio Adonnino, Brandon Lofts, Jennifer Waldo, Julian Halmai, Orrin Devinsky, Kyle Fink, X Shawn Liu.

DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2+/- mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.

DOI: https://doi.org/10.1038/s41467-025-67222-5