bims-mimead 2026-09-20 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–09–20
six papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

ALMS1 regulates primary cilia signaling in adipogenesis.
Effects of Pep19 on adipose tissue distribution and metabolic parameters in adults with obesity: A randomized, double-blind, placebo-controlled trial.
Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.
Changes in plasma levels of a selected panel of miRNAs do not explain the shift from cholesterol-synthesizer to cholesterol-absorber phenotype in men with abdominal obesity after diet-induced weight loss.
Reduction in T-Cell Mitochondrial Respiratory Capacity After Reaching a Weight Loss Plateau.
Global GPR75 deficiency protects against diet-induced obesity through central and peripheral mechanisms.

Mol Biol Cell. 2026 Sep 16. mbcE26060296

ALMS1 regulates primary cilia signaling in adipogenesis.

Mark D Lee, Stephanie Dudics Giagnocavo, Kiley J Campora, Rohan Menon, Keren I Hilgendorf.

Metabolic diseases such as type 2 diabetes are often associated with adipose tissue dysfunction and obesity. Disorders of the primary cilium, or ciliopathies, can lead to obesity and the development of metabolic disease, as these signaling organelles regulate both the satiety pathway and adipose tissue expansion. Alström syndrome, a ciliopathy caused by loss of function of the Alms1 gene, is linked to hyperphagia, obesity, and early-onset type 2 diabetes, though how ALMS1 functions throughout the body to maintain energy homeostasis and metabolic health remains unclear. Here we demonstrate that ALMS1 loss in cultured preadipocytes and primary adipocyte progenitor cells from visceral, but not subcutaneous, mouse white adipose tissue depots inhibits their ability to undergo adipogenesis. Isolated primary adipocyte progenitor cells and cultured preadipocytes exhibit reduced ciliation and decreased centriole cohesion in the absence of ALMS1. Further, ALMS1 knockout preadipocytes retain the ciliary localization of G protein-coupled receptors known to influence adipogenesis, yet fail to undergo the changes in adipogenesis expected with their activation, consistent with a defect in ciliary transduction downstream of receptor localization. These findings demonstrate a new role for the ciliopathy gene Alms1 in directly regulating adipose tissue expansion through the regulation of ciliary signals required for adipogenesis.

DOI: https://doi.org/10.1091/mbc.E26-06-0296
iScience. 2026 Oct 16. 29(10): 117471

Effects of Pep19 on adipose tissue distribution and metabolic parameters in adults with obesity: A randomized, double-blind, placebo-controlled trial.

Davi Vantini, João Roberto de Sá, Roseli O S Sarni, Sonia Hix, Fabio L Filho, Raphael Ruiz, Ricardo A Remer, Arnon Krongrad, Luiz Felipe Martucci, Emer S Ferro, Andrea S Heimann, Fernando L A Fonseca.

  Whether modulation of adipose tissue distribution alone can improve insulin sensitivity independently of weight loss remains unclear. In this randomized, double-blind, placebo-controlled 90-day trial, we investigated whether adults with obesity could achieve metabolic improvement through modulation of adipose tissue distribution independent of weight loss. Fifty-six participants received oral placebo or Pep19 (5 or 10 mg daily). Regional fat distribution and metabolic parameters were assessed longitudinally. Pep19 at 10 mg reduced central adiposity, as demonstrated by a reduced android-to-gynoid fat ratio and decreased abdominal skinfold thickness, without affecting body weight, caloric intake, or physical activity. Glycated hemoglobin (HbA1c) and HOMA-IR were significantly reduced, despite unchanged fasting glucose, indicating improved insulin sensitivity. These findings suggest that Pep19 promotes favorable changes in adipose tissue distribution accompanied by improvements in insulin sensitivity independent of significant weight loss, supporting further evaluation in larger and longer-term clinical studies.

Keywords:  HbA1c; cardiometabolic health; central adiposity; diabetes; insulin resistance; intracellular peptides; obesity; randomized trial

DOI:  https://doi.org/10.1016/j.isci.2026.117471
Nat Metab. 2026 Sep 15.

Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.

Jonas Petersen, Christoffer Merrild, Stephanie Kjærulff Holm, Nigel Kurgan, Shad Hassan, Cecilie Vad Mathiesen, Stina Börchers, Charlotte Svendsen, Sergio D'Anna, Nicoline R Andersen, Anders Bue Klein, Andreas M Fritzen, Atul S Deshmukh, Tune H Pers, Christoffer Clemmensen.

Peptide multi-receptor agonists have advanced obesity treatment, yet challenges remain in achieving maximal weight loss and metabolic control, especially in patients with obesity and type 2 diabetes. Here we demonstrate enhanced metabolic benefits of a combination therapy with retatrutide, a unimolecular GLP-1R/GIPR/GCGR tri-agonist, and cagrilintide, an AMLNR/CALCR co-agonist, in diet-induced obese male rats. Daily co-administration produces dose-dependent reductions in body weight and food intake that exceed both equimolar monotherapies and matched-dose comparator combinations incorporating semaglutide or tirzepatide. The combination therapy also improves circulating markers of metabolic health, including cholesterol, triglycerides and insulin levels. Pair-feeding and weight-matching studies reveal that the enhanced weight loss cannot be explained by reduced food intake alone and enable discrimination between weight-loss-dependent and drug-specific molecular responses. Plasma proteomic profiling highlights enrichment of bioenergetic processes with the combination therapy, whereas brain transcriptomic profiling identifies convergent central neuronal programmes linked to energy balance regulation. Collectively, our preclinical findings support five-receptor polypharmacology as a strategy for efficaciously lowering body weight and provide guidance for the design of next-generation unimolecular multi-receptor agonists.

DOI: https://doi.org/10.1038/s42255-026-01603-y
Int J Obes (Lond). 2026 Sep 15.

Changes in plasma levels of a selected panel of miRNAs do not explain the shift from cholesterol-synthesizer to cholesterol-absorber phenotype in men with abdominal obesity after diet-induced weight loss.

Maurice C J M Konings, Ronald P Mensink, Peter J Joris, Mark V Boekschoten, Casper G Schalkwijk, Alfons J H M Houben, Jogchum Plat.

BACKGROUND: Individuals with overweight or obesity exhibit a cholesterol-synthesizer phenotype (high plasma lathosterol/campesterol ratio). Previously, we have reported that weight loss in men with abdominal obesity shifted this phenotype towards a cholesterol-absorber (low plasma ratio) profile. Given the role of microRNAs (miRNA) in cholesterol metabolism, we hypothesized that this shift is mediated by changes in regulatory miRNAs.
OBJECTIVE: To assess whether a panel of pre-selected plasma miRNAs mediates the phenotype switch from cholesterol-synthesizer to cholesterol-absorber following weight loss.
METHODS: An untargeted serum miRNA screening approach was performed. From an existing database (N = 367), samples from participants with the highest (N = 8) and the lowest (N = 8) plasma lathosterol/campesterol ratios were selected. Three microRNAs associated with cholesterol-synthesizers and three miRNAs associated with cholesterol-absorbers were identified. Changes in these miRNAs were then evaluated in a well-controlled weight-loss study. For this, men with abdominal obesity were randomized into a no-weight-loss control group (N = 26) and a weight-loss group (N = 23) that lost 10.3 kg body weight. Pre- and post-intervention, plasma microRNA levels were measured.
RESULTS: The screening identified miR-486-5p, miR-320b-3p and miR-185-5p as associated with the cholesterol-synthesizer phenotype, and miR-4529-3p, miR-3613-5p and miR-6776-5p with the cholesterol-absorber phenotype. One miRNA assay (miR-4529-3p) was unreliable and excluded from further analysis. Although the expected phenotype shift after weight loss was observed, changes in plasma miRNA levels were not significantly different between the two groups.
CONCLUSION: In men with abdominal obesity, these five plasma miRNAs did not contribute to the observed phenotype switch from cholesterol-synthesizer towards cholesterol-absorber following weight loss.

DOI: https://doi.org/10.1038/s41366-026-02217-w
Diabetes. 2026 Sep 18. pii: db260304. [Epub ahead of print]

Reduction in T-Cell Mitochondrial Respiratory Capacity After Reaching a Weight Loss Plateau.

Ana P Valencia, Arthur F Brandao, Susan J Melhorn, Mary Rosalynn B De Leon, David J Marcinek, Ellen A Schur.

Experiencing an involuntary weight loss plateau is common after behavioral weight loss. During such periods, sustained negative energy balance activates counterregulatory mechanisms that restore energy balance and may slow further weight loss. However, the cellular bioenergetic changes occurring specifically during a spontaneous weight loss plateau have not been investigated. We studied mitochondrial respiratory capacity in peripheral mononuclear cell populations from participants with obesity, both before and after an intensive lifestyle intervention (ILI). Body weight was tracked continuously over 18 months using a remote electronic scale, enabling retrospective categorization of outcome measures by weight loss phases: active weight loss (aWL), plateau (PL), or regain (RG). Differences in mitochondrial respiration were observed in T cells but not in monocytes across these phases. During aWL, mitochondrial respiratory capacity was similar to pre-ILI; however, basal, ATP-linked, maximal, and spare respiratory capacity were significantly lower during the PL and RG phases. In addition, ATP-linked respiration was lower in the PL and RG, despite higher mitochondrial citrate synthase activity in the PL relative to pre-ILI. These results indicate that T-cell bioenergetics may be responsive to shifts in energy balance during weight reduction. The novel phase-specific classification used in this study uncovers dynamic bioenergetic adaptations that may contribute to a weight loss plateau.
ARTICLE HIGHLIGHTS: Weight loss is a dynamic process, characterized by transitions between active weight loss, plateau, and regain, yet underlying metabolic features across these phases remain poorly defined. This study tested whether mitochondrial bioenergetics in peripheral mononuclear cells differ in humans across weight loss phases during behavioral weight loss. Mitochondrial respiratory capacity of T cells is significantly reduced during plateau and regain phases, despite an increase in mitochondrial content. Phase-based classification of weight change reveals bioenergetic differences in T cells that are associated with transitions in energy balance within the weight-reduced state.

DOI: https://doi.org/10.2337/db26-0304
Mol Metab. 2026 Sep 18. pii: S2212-8778(26)00128-6. [Epub ahead of print] 102444

Global GPR75 deficiency protects against diet-induced obesity through central and peripheral mechanisms.

Xiaoyun Cao, Vanna Chhay, Thi Tun Thi, Hui Li, Yu Shi, Yifan Wang, Yilin Min, Renhua Song, Kai Yan Cheng, Yang Yang, Justin Jong-Leong Wong, Haojie Yu.

Loss-of-function variants of GPR75 are associated with protection against obesity in humans; however, the mechanisms through which GPR75 regulates whole-body energy homeostasis remain incompletely understood. Here, we generated Gpr75 global knockout (GKO) mice and performed comprehensive metabolic phenotyping under chow and high-fat diet (HFD) conditions. Despite high expression of GPR75 in the brain, male GKO mice exhibited unchanged food intake during the period when body weights began to diverge. Instead, GPR75 deficiency resulted in reduced whole-body energy expenditure and an elevated respiratory exchange ratio, indicating decreased fat utilization. Notably, male, but not female, GKO mice displayed markedly impaired intestinal lipid absorption, reduced chylomicron output, and increased fecal lipid excretion, consistent with limited dietary lipid assimilation under HFD feeding. To define the tissue-specific contributions of GPR75, we next examined hepatocyte-, intestinal epithelial-, endothelial/ hematopoietic-, and AgRP neuron-specific Gpr75 knockout mice. Deletion of Gpr75 in hepatocytes (Alb-Cre), intestinal epithelium (Vil-Cre), or endothelial/hematopoietic lineages (Tie2-Cre) did not reproduce the pronounced protection against HFD-induced weight gain observed in GKO mice. In contrast, AgRP neuron-specific deletion reduced body weight by approximately 10%-12% in male and female mice and decreased white adipose depot mass by 27%-50%, establishing AgRP neurons as a specific neuronal population through which GPR75 contributes to body-weight regulation. However, the magnitude of this phenotype remained substantially smaller than that observed in global GPR75-deicient mice. Together, our findings demonstrate that GPR75 regulates diet-induced obesity through both central and peripheral mechanisms. AgRP-neuronal GPR75 contributes to body-weight regulation in both sexes, whereas global GPR75 deficiency additionally impairs intestinal lipid assimilation in males through a mechanism not recapitulated by deletion in the tested peripheral cell populations. These complementary effects likely contribute to the pronounced resistance to diet-induced obesity and hepatic steatosis observed in global GPR75-deficient mice and further support GPR75 as a therapeutic target for obesity and associated metabolic liver disease.

DOI: https://doi.org/10.1016/j.molmet.2026.102444