bims-mimead 2025-06-08 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–06–08
eleven papers selected by
Rachel M. Handy, University of Guelph

The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity.
Adipose tissue protein kinase D (PKD): regulation of signalling networks and its sex-dependent effects on metabolism.
Individual response to lifestyle interventions: a pooled analysis of three long-term weight loss trials.
Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity.
Beneficial Effects of Carbohydrate Restriction in Type 2 Diabetes Can Be Traced to Changes in Hepatic Metabolism.
Benzyl isothiocyanate ameliorates hepatic insulin resistance in mice with high-fat diet-induced nonalcoholic fatty liver disease.
Multi-organ multi-omic and gut microbiome markers of fat and sucrose dietary oversupply in cardiometabolic disease.
Uncovering the role of Gpr45 in obesity regulation.
Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy.
G Protein Coupled Estrogen Receptor Signaling Maintains β Cell Identity in Female Mice.

J Clin Invest. 2025 Jun 05. pii: e175566. [Epub ahead of print]

The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity.

Pradip K Saha, Robert Sharp, Aaron R Cox, Rabie Habib, Michael J Bolt, Jessica B Felix, Claudia E Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M Hartig.

  White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic co-morbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved microRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed high fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits pro-fibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an anti-fibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.

Keywords:  Adipose tissue; Cell biology; Fibrosis; Metabolism; Noncoding RNAs

DOI:  https://doi.org/10.1172/JCI175566
Am J Physiol Endocrinol Metab. 2025 Jun 02.

Adipose tissue protein kinase D (PKD): regulation of signalling networks and its sex-dependent effects on metabolism.

Mark C Renton, Sean J Humphrey, Tim Connor, Sheree D Martin, Krystal Kemerer, Hilary Fernando, Christopher S Shaw, David E James, Kirsten F Howlett, Sean L McGee.

  The protein kinase D (PKD) family of three highly homologous isoforms (PKD1, PKD2, and PKD3) are implicated as nutrient sensing signalling kinases that regulate the response of adipose and other tissues to the nutrient environment. However, the physiological role of adipose tissue PKD and its downstream cellular signalling targets are not well characterised. Here we employed phosphoproteomics was performed to elucidate signalling events downstream of PKD activation in differentiated 3T3-L1 adipocytes using a triple isoform siRNA knockdown model. This revealed PKD-regulated pathways including insulin and cAMP signalling, which control metabolic responses in adipose tissue. An adipose tissue-specific and inducible dominant negative PKD (atDNPKD) mouse model that achieves functional inhibition of all three PKD isoforms was generated to assess the function of adipose PKD on whole-body metabolism in vivo in both male and female mice. Insulin-stimulated suppression of lipolysis was blunted in male, but not female, atDNPKD mice compared to control mice. Female, but not male, atDNPKD mice had higher fasting insulin but normal insulin action. Male atDNPKD mice showed greater sensitivity to the β3-adrenergic receptor agonist CL316,243 on measures of lipolysis and energy expenditure, and displayed greater fat oxidation during fasting. During refeeding, male atDNPKD mice consumed less food and took longer to regain body weight lost during fasting. These effects were not observed in female mice. These findings indicate that PKD provides sex-dependent fine-tuning control of cAMP signalling in adipose tissue that is important for the coordination of energy balance during fasting and refeeding.

Keywords:  Phopshoproteomics; adipose tissue; feeding behaviour; kinase Signaling

DOI:  https://doi.org/10.1152/ajpendo.00391.2024
Eur J Prev Cardiol. 2025 Jun 05. pii: zwaf308. [Epub ahead of print]

Individual response to lifestyle interventions: a pooled analysis of three long-term weight loss trials.

Anat Yaskolka Meir, Gal Tsaban, Ehud Rinott, Hila Zelicha, Dan Schwarzfuchs, Yftach Gepner, Assaf Rudich, Ilan Shelef, Matthias Blüher, Michael Stumvoll, Uta Ceglarek, Berend Isermann, Nora Klöting, Maria Keller, Peter Kovacs, Lu Qi, Dong D Wang, Liming Liang, Frank B Hu, Meir J Stampfer, Iris Shai.

   AIMS: We explored the manifestations of individual weight loss (WL) response to long-term lifestyle interventions on cardiometabolic risk.
METHODS AND RESULTS: We pooled data from three large long-term lifestyle WL-intervention trials: 24-month DIRECT (ClinicalTrials.gov: NCT00160108; n = 322; 87% adherence), 18-month CENTRAL (ClinicalTrials.gov: NCT01530724; n = 278; 86% adherence), and 18-month DIRECT PLUS (ClinicalTrials.gov: NCT03020186; n = 294; 89% adherence). We analyzed longitudinal changes in cardiometabolic risk markers, including anthropometrics, blood biomarkers, and magnetic-resonance-imaging-assessed fat depots, and measured DNA-methylation, proteomics, and metabolomics. Among trial completers (n = 761, mean age = 50.4 years; 89% men, baseline body-mass-index = 30.1 kg/m2), mean WL was -3.3 kg (-3.5%). We classified participants as Successful-WL (36%) with relative-WL > 5%, WL-Resistant (28%) who did not lose or gained weight, and Moderate-WL (36%) with WL between 0% and 5%. Successful-WL achieved the greatest improvements in multiple health indicators. However, the WL-Resistant also showed some significant improvements, with increased high-density-lipoprotein-cholesterol (HDLc) and decreased leptin and visceral fat (P < 0.05 vs. baseline). Overall, each 1 kg sustained lifestyle-induced WL was associated with improvements in lipid markers and insulin resistance [HDLc (+1.44%), triglycerides (-1.37%), insulin (-2.46%), HOMA-IR (-2.71%), leptin (-2.79%)] and intrahepatic-fat regression (-0.49 absolute-units)] and modest but significant change in systolic and diastolic blood pressures (-0.26% and -0.36%). We identified 12 significant methylation sites that are associated with Successful-WL (FDR < 0.05; AUC = 0.73).
CONCLUSION: While only ∼one-third of individuals achieved long-term WL, the Moderate-WL and WL-Resistant individuals could benefit improvements in visceral adiposity and cardiometabolic risk by shifting towards a healthy lifestyle pattern, beyond WL. Site-pecific DNA methylation may predict an individual's likelihood of successful WL.
REGISTRATION: NCT00160108, NCT01530724, NCT03020186.

Keywords:  Epigenetics; Intervention trials; Lifestyle; Metabolomics; Nutrition; Proteomics; Weight-loss

DOI:  https://doi.org/10.1093/eurjpc/zwaf308
Nat Metab. 2025 Jun 03.

Cysteine depletion triggers adipose tissue thermogenesis and weight loss.

Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Prabhakar Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Bandy Chen, Maxim N Artyomov, Fahmeed Hyder, Tamas L Horvath, Marc Schneeberger, Yuki Sugiura, Vishwa Deep Dixit.

Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

DOI: https://doi.org/10.1038/s42255-025-01297-8
J Clin Invest. 2025 May 30. pii: e190765. [Epub ahead of print]

Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity.

Brian I Park, Andrew R Reeves, Ying Zhu, Robin A Wilson, Sophia C Fernandes, Kimberly K Buhman, Kelli A Lytle, Michael D Jensen, Andrew S Greenberg.

  Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

Keywords:  Adipose tissue; Endocrinology; Insulin; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI190765
J Clin Endocrinol Metab. 2025 May 31. pii: dgaf324. [Epub ahead of print]

Beneficial Effects of Carbohydrate Restriction in Type 2 Diabetes Can Be Traced to Changes in Hepatic Metabolism.

Barbara A Gower, Marian L Yurchishin, Amy M Goss, John Knight, William T Garvey.

   CONTEXT: Carbohydrate restriction benefits metabolic health in patients with type 2 diabetes (T2D), possibly through changes in hepatic metabolism.
OBJECTIVE: To test the hypothesis that the ketogenic diet (KD) would decrease de novo lipogenesis (DNL) and liver fat, which would be associated with restored beta-cell function.
METHODS: Participants were 57 adults with mild T2D. A hyperglycemic clamp was used to assess acute C-peptide response (ACP), and magnetic resonance imaging to assess hepatic fat fraction, at baseline and after 12 weeks of either a eucaloric KD (∼9% energy from carbohydrate, 65% energy from fat) or a eucaloric low-fat diet (LFD) (∼55% energy from carbohydrate, 20% energy from fat).
RESULTS: The KD led to decreases in pyruvate (-23%, P<0.001) and palmitoleic acid, a marker of DNL (-32%, P<0.01). Participants on the KD had higher fasting glucagon (25%, P<0.05) and lower liver fat (28%, P<0.05) at week 12 than those on the LFD. In all combined, the change in liver fat was positively associated with the change in pyruvate (r = 0.45, P=0.05), and inversely associated with changes in glucagon (r = -0.34, P<0.05), the glucagon to C-peptide ratio (r = -0.44, P<0.01), and ACP (r = -0.34, P<0.05). The change in ACP was inversely associated with the change in pyruvate in the KD group (r = -0.5, P<0.05), but not in the LFD group.
CONCLUSIONS: A shift in hepatic metabolism to favor fat oxidation over DNL may underlie the beneficial effects of carbohydrate restriction on hepatic steatosis and glucose-induced insulin secretion.

Keywords:  beta-cell; de novo lipogenesis; ketogenic diet; liver fat; pyruvate; type 2 diabetes

DOI:  https://doi.org/10.1210/clinem/dgaf324
J Nutr Biochem. 2025 May 29. pii: S0955-2863(25)00144-5. [Epub ahead of print] 109981

Benzyl isothiocyanate ameliorates hepatic insulin resistance in mice with high-fat diet-induced nonalcoholic fatty liver disease.

Chia-Wen Lo, Jyun-Lin Lee, Wei-Ting Tsai, Chin-Shiu Huang, Ya-Chen Yang, Chong-Kuei Lii, Haw-Wen Chen.

  The global prevalence of overweight and obesity has risen sharply over the past few decades as a result of excess calorie intake and sedentary lifestyles. Obesity increases the risk for various metabolic disorders, such as hyperlipidemia, fatty liver disease, and diabetes mellitus. Isothiocyanates, which are abundant in cruciferous vegetables, have been shown to exhibit anti-cancer, anti-inflammatory, and antioxidant properties. However, the efficacy of benzyl isothiocyanate (BITC) in preventing the adverse effects of obesity, such as hepatic steatosis and insulin resistance, remains uncertain. To address this knowledge gap, we assessed whether BITC protects against hepatic insulin resistance by using primary mouse hepatocytes and AML12 cells treated with palmitic acid (PA) and mice fed a high-fat diet supplemented with cholesterol and cholic acid (HFCCD). We found that the impairments in insulin sensitivity caused by PA, such as decreases in the phosphorylation of insulin receptor substrate (IRS) 1 (Tyr608), Akt, glycogen synthase kinase (GSK) 3β, and FOXO1 and increases in the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK) mRNA in hepatocytes, were mitigated by pretreatment with BITC. BITC also attenuated PA-induced hepatic lipid accumulation and reactive oxygen species production. In vivo, BITC significantly reduced blood glucose levels and the HOMA-IR and inhibited hepatic lipid accumulation, IRS1 phosphorylation at Ser307, and G6Pase and PEPCK expression compared with that in mice fed the HFCCD alone. These results show that BITC ameliorates the lipotoxicity associated with insulin resistance by activating the IR/IRS/Akt/FOXO1 and GSK3β pathways, which leads to decreased gluconeogenesis and increased glycogen synthesis.

Keywords:  Benzyl isothiocyanate; Gluconeogenesis; Glycogenesis; Insulin resistance; Nonalcoholic fatty liver diseases

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109981
iScience. 2025 Apr 18. 28(4): 111887

Multi-organ multi-omic and gut microbiome markers of fat and sucrose dietary oversupply in cardiometabolic disease.

Ren Ping Liu, Alistair Senior, Zhen Bao, Yen Chin Koay, Andrew Holmes, John F O'Sullivan.

  Cardiometabolic disease is the greatest challenge facing global health. Increasingly, evidence suggests that Western diet comprising an over-supply of energy from fat and sucrose leads to obesity, insulin resistance, hypertension, and cardiovascular disease. Traditional preclinical animal studies of cardiometabolic disease often adopt a reductionist approach, focusing on individual components. To overcome this, we comprehensively assessed cardiometabolic phenotypes- anthropometric, physiological, and metabolic- along with the molecular changes consequent upon fat or sucrose dietary oversupply, or both in male C57BL/6J mice. Molecular assessment included measurement of the gut microbiome and several metabolite pools including plasma, heart, liver, and gut contents (cecal and fecal). In these mice, we identified key changes across phenotypes, metabolites, microbiota, and their interrelationship, and synthesized all the data into four distinct phenogroups that explain the variance across cardiometabolic parameters. These phenogroups provide insight into inter-organ regulation of Western diet-dependent cardiometabolic phenotypes, highlighting important avenues for further study.

Keywords:  Diet; Microbiome

DOI:  https://doi.org/10.1016/j.isci.2025.111887
Mol Metab. 2025 May 29. pii: S2212-8778(25)00081-X. [Epub ahead of print] 102174

Uncovering the role of Gpr45 in obesity regulation.

Eva O Karolczak, Chia Li, Ivan C Alcantara, Isabel M Cohen, Claire Gao, Cuiying Xiao, Abigail I Goldschmidt, Cynthia A Pinkus, Junjie Li, Monica M Li, Ryan M Esquejo, Jean-Philippe Fortin, Kendra K Bence, Marc L Reitman, Michael J Krashes.

OBJECTIVES: G protein-coupled receptors (GPCRs) are the most druggable targets in biology due to their cell-type specificity, ligand binding, and cell surface accessibility. Underscoring this, agonists for GPCRs have recently revolutionized the treatment of diabetes and obesity. The rampant success of these compounds has invigorated interest in identifying additional GPCRs that modulate appetite and body weight homeostasis. One such potential therapeutic target is G-protein couped receptor 45 (Gpr45), an orphan GPCR expressed both centrally and peripherally. We aimed to explore the role of Gpr45 as well as neurons expressing Gpr45 in energy balance.
METHODS: Three novel transgenic mouse models were engineered to investigate the functional contribution of Gpr45 to body weight and appetite regulation: 1) a global Gpr45 knockout, 2) a conditional floxed Gpr45 allele, and 3) a Gpr45-CreERT2 knock-in. Metabolic profiling was performed in global Gpr45 knockout animals including body weight, food intake, body mass, energy expenditure, and body temperature measurements. Animals harboring a conditional floxed Gpr45 allele were bred to mice expressing Cre-recombinase in excitatory neurons labeled via Vesicular glutamate transporter 2 (Vglut2), inhibitory cells expressing Vesicular GABA transporter (Vgat), or neurons marked by the transcription factor Single-minded 1 (Sim1) and monitored for body weight and food consumption. Additionally, floxed Gpr45 mice were bilaterally injected with AAV-Cre targeting the paraventricular nucleus of the hypothalamus (PVH) and body weight and food intake were evaluated. The Gpr45-CreERT2 knock-in model was used to express chronic and acute actuators to the PVH to assess the role of PVHGpr45 neurons in energy homeostasis.
RESULTS: Global Gpr45 disruption caused marked weight gain, increased food intake and fat mass, but no detectable alterations in core temperature or energy output. Selective deletion of Gpr45 from Sim1+ or excitatory Vglut2+ but not inhibitory Vgat+, neurons produced obesity and hyperphagia. Targeted deletion of Gpr45 from the PVH phenocopies these metabolic changes suggesting a major site of action of Gpr45 signaling is glutamatergic neurons residing in the PVH. Tetanus toxin light chain (TeNT) was used to permanently silence PVHGpr45 neuronal activity in Gpr45-CreER mice leading to rapid weight accumulation and escalated food intake. These experiments highlight the critical role of both Gpr45 signaling and neural network activity in the regulation of body weight and appetite. A mutated version of the bacterial sodium channel, NaChBac, was used to constitutively activate PVHGpr45 neuronal activity in Gpr45-CreER mice with limited to no effect on body weight and food consumption, implicating redundant circuitry acting in concert to bias weight loss protection. Acute chemogenetic stimulation of PVHGpr45 neurons durably suppressed food intake regardless of caloric need state or food palatability demonstrating the capacity of these cells to curb appetite.
CONCLUSIONS: Gpr45 is a putative therapeutic candidate that could be targeted to combat obesity and overeating.

DOI: https://doi.org/10.1016/j.molmet.2025.102174
bioRxiv. 2025 May 19. pii: 2025.05.15.654390. [Epub ahead of print]

Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy.

Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar.

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen-related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigation of dystrophy in DMD is not known. We have investigated ERRα signaling in pre-clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in vitro findings, transgenic ERRα overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl 2 injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERRα and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defect in these cells. Loss of ERRα and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERRα overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, and boosted regeneration after BaCl2 injury in dystrophic muscle. Our studies demonstrate a pro-regenerative role of ERRα and its deficiency in dystrophic muscles and its MuSCs. ERRα restoration could be a therapeutic strategy for DMD through angio-metabolic gene program.

DOI: https://doi.org/10.1101/2025.05.15.654390
bioRxiv. 2025 May 15. pii: 2025.05.12.652914. [Epub ahead of print]

G Protein Coupled Estrogen Receptor Signaling Maintains β Cell Identity in Female Mice.

Madeline R McLaughlin, Preethi Krishnan, Wenting Wu, Cameron Rostron, Kara Orr, Lata Udari, Jacqueline Del Carmen Aquino, Amanda Fisher, Tatsuyoshi Kono, Kok Lim Kua, Carmella Evans-Molina.

Type 2 diabetes (T2D) arises in the context of obesity and overnutrition; however, additional demographic features including age and biological sex contribute to T2D risk. Estradiol (E2) is thought to play a protective metabolic role that may govern sex differences in the development of T2D. The mechanisms by which E2 exerts these effects and the impact of reduced E2 signaling in β cells during menopause remain incompletely understood. We analyzed publicly available whole islet transcriptome datasets from female and male cadaveric donors and showed significant age-related modulation of gene expression, including changes in pathways related to β cell function, in islets from female donors. Importantly, these patterns were not observed in islets from male donors. To test the in vivo relationship between E2 signaling and β cell function, 10-week- old female C57BL6/J mice underwent an ovariectomy (OVX) or sham (CTR) surgery, followed by 4 weeks of high-fat diet (HFD) treatment. HFD-OVX mice exhibited obesity-induced glucose intolerance, increased α cell mass, and reduced expression of β cell identity markers. Furthermore, ex vivo treatment of islets with the G protein coupled estrogen receptor (GPER)- specific agonist G-1 restored β cell identity gene expression. Together, these data identify a novel connection between GPER signaling and β cell identity and suggest that menopausal loss of E2 signaling through GPER may be linked with loss of β cell identity.

DOI: https://doi.org/10.1101/2025.05.12.652914