bims-mimead 2025-09-21 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–09–21
nine papers selected by
Rachel M. Handy, University of Guelph

Covariation MS uncovers a protein that controls cysteine catabolism.
Prostaglandin E2 inhibits adipogenesis through the cilia-dependent activation of ROCK2.
Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.
Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure.
The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity.
Vasoactive Intestinal Peptide: Another Player in Adipose Tissue Blood Flow Regulation?
Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals.
The liver clock modulates circadian rhythms in white adipose tissue.
Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice.

Nature. 2025 Sep 17.

Covariation MS uncovers a protein that controls cysteine catabolism.

Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.

The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.

DOI: https://doi.org/10.1038/s41586-025-09535-5
J Cell Sci. 2025 Sep 16. pii: jcs.264193. [Epub ahead of print]

Prostaglandin E2 inhibits adipogenesis through the cilia-dependent activation of ROCK2.

Mark D Lee, Keren I Hilgendorf.

  Functional adipose tissue is essential for maintaining systemic metabolic homeostasis. Dysfunctional adipose tissue, characterized by increased fibrosis, hypoxia, and chronic inflammation, is often associated with obesity and promotes the onset of metabolic disease such as type 2 diabetes. During nutrient excess, adipose tissue function can be preserved by the generation of new adipocytes from adipocyte stem cells, illustrating the importance of identifying the physiological regulators of adipogenesis. Here, we discover a cilia-localized signaling pathway through which the pro-inflammatory lipid metabolite prostaglandin E2 (PGE2) suppresses adipogenesis. We demonstrate that PGE2 specifically signals through the E-type prostaglandin receptor 4 (EP4) localized to the primary cilium of adipocyte stem cells. Activation of ciliary EP4 initiates a cAMP-independent signaling cascade that activates the Rho-associated protein kinase 2 (ROCK2) resulting in the retention of actin stress fibers that prevent adipogenesis. These findings uncover a compartmentalized regulatory mechanism of adipogenesis by which primary cilia alter whole-cell physiology, cell fate, and ultimately adipose tissue expansion in response to an inflammatory hormone, offering insight into how chronic inflammation may contribute to adipose tissue dysfunction and metabolic disease progression.

Keywords:  Adipogenesis; Cytoskeleton; Inflammation; PGE2; Primary cilia; ROCK2

DOI:  https://doi.org/10.1242/jcs.264193
Nature. 2025 Sep 17.

Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.

Xuejing Liu, Anyuan He, Dongliang Lu, Donghua Hu, Min Tan, Abenezer Abere, Parniyan Goodarzi, Bilal Ahmad, Brian Kleiboeker, Brian N Finck, Mohamed Zayed, Katsuhiko Funai, Jonathan R Brestoff, Ali Javaheri, Patricia Weisensee, Bettina Mittendorfer, Fong-Fu Hsu, Paul P Van Veldhoven, Babak Razani, Clay F Semenkovich, Irfan J Lodhi.

Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1-/- mice are not obese1-5, consistent with the existence of alternative mechanisms of thermogenesis6-8. Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids9 and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid β-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle.

DOI: https://doi.org/10.1038/s41586-025-09517-7
Mol Metab. 2025 Sep 11. pii: S2212-8778(25)00157-7. [Epub ahead of print] 102250

Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure.

Andrea R Ortiz, Kevin Nay, Brittany A Stork, Adam M Dean, Sean M Hartig, Cristian Coarfa, Surafel Tegegne, Christopher Rm Asquith, Daniel E Frigo, Brian York, Anthony R Means, Mark A Febbraio, John W Scott.

  Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic metabolism, and a coordinator of macrophage-mediated inflammatory responses. Here, we demonstrate that myeloid-specific Camkk2 deficient mice are protected from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects are associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure. Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.

Keywords:  Glucose homeostasis; Inflammation; Insulin resistance; Kinase signaling; Liver steatosis

DOI:  https://doi.org/10.1016/j.molmet.2025.102250
Cell Mol Immunol. 2025 Sep 18.

The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity.

Marc P Hübner, Dennis de Coninck, Benjamin Lenz, Jayagopi Surendar, Marianne Koschel, Narcisse Victor Tchamatchoua Gandjui, Beng Amuam Andrew, Lucy Cho Nchang, Anita Obi Bate Ebob, Fanny Fri Fombad, Lisa Marie Springer, Lars Eppe, Frank A Schildberg, Samuel Wanji, Achim Hoerauf, Alexander Pfeifer, Indulekha Karunakaran.

  Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELMα+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1β and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.

Keywords:  Helminths; IL-9 signaling; Inflammasome; Inflammation; Obesity; insulin resistance

DOI:  https://doi.org/10.1038/s41423-025-01340-4
Microcirculation. 2025 Oct;32(7): e70026

Vasoactive Intestinal Peptide: Another Player in Adipose Tissue Blood Flow Regulation?

Richard Sotorník, Julie Ménard, Pascal Brassard, Maude Gagnon-Auger, Jean-Patrice Baillargeon, Jean-Luc Ardilouze.

   OBJECTIVES: In healthy people, adipose tissue blood flow (ATBF) rises postprandially; however, in one third of them, this response is altered. These people are characterized by prolonged postprandial lipemia and higher cardiometabolic risk. Vasoactive intestinal peptide (VIP) is a gut neurotransmitter with a vasodilatory effect. The aim of the study was to assess the role of VIP in ATBF regulation and its postprandial blunting.
METHODS: Plasma VIP and ATBF (133Xenon washout technique) were measured during a 75 g oral glucose load in 16 healthy participants. ATBF was monitored in 12 individuals during in situ microinfusion of incremental doses of VIP (10-7, 10-6, 10-5 mol L-1).
RESULTS: Oral glucose induced no change in plasma VIP. Post-glucose ATBF measures identified 7 non-responders (peak blood flow < 50% of fasting values) and 9 responders. Compared to baseline (2.50 [1.96-3.59] mL·100 g-1 min-1), local microinfusion of VIP increased ATBF dose-dependently: 2.67 [2.18-3.89]; 4.35 [3.33-4.65]; and 7.91 [6.59-9.88] mL·100 g-1 min-1 (p < 0.0001) with a non-significant lower response to VIP in non-responders.
CONCLUSIONS: Our findings show a potent vasodilatory effect of VIP in adipose tissue and suggest that individuals with a blunted ATBF response to glucose load have a lower response. Whether the local unresponsiveness to VIP participates in this non-responder status has to be confirmed in larger studies.

Keywords:  133Xenon washout; adipose tissue blood flow; gastrointestinal tract; vasoactive intestinal peptide

DOI:  https://doi.org/10.1111/micc.70026
Metabolism. 2025 Sep 13. pii: S0026-0495(25)00260-4. [Epub ahead of print]173 156391

Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals.

Anna Giannakogeorgou, Sabine Kahl, Cesare Granata, Geronimo Heilmann, Lucia Mastrototaro, Bedair Dewidar, Pavel Bobrov, Irene Esposito, Aslihan Yavas, Sandra Trenkamp, Frank A Granderath, Matthias Schlensak, Christos S Mantzoros, Michael Roden, Patrick Schrauwen.

   BACKGROUND AND PURPOSE: Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH.
METHODS: Humans without (n = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation.
RESULTS: Serum GDF15 correlated negatively with M-value (r = -0.35, p = 0.017) and NEFA suppression (r = -0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m2) or absence of hepatic fibrosis (n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m2). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (FP; r = 0.35, p = 0.035) and maximal coupled (FNSP; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FNP in persons with fibrosis (r = -0.48, p = 0.022).
CONCLUSIONS: In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.

Keywords:  Fibrosis; Growth differentiation factor 15; Insulin resistance; Liver; Mitochondria; Obesity

DOI:  https://doi.org/10.1016/j.metabol.2025.156391
Mol Metab. 2025 Sep 12. pii: S2212-8778(25)00156-5. [Epub ahead of print] 102249

The liver clock modulates circadian rhythms in white adipose tissue.

Ivan Vlassakev, Christina Savva, Gianluca Renzi, Hema S Ilamathi, Doste R Mamand, Jacob G Smith, Carolina M Greco, Christopher Litwin, Qing Zhang, Leandro Velez, Angela Ma, Martin O Bergo, Oscar P B Wiklander, Pura Muñoz-Cánovez, Niklas Mejhert, Marcus Seldin, Johan L M Björkegren, Paolo Sassone-Corsi, Kevin B Koronowski, Salvador Aznar Benitah, Paul Petrus.

  Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a hepatocyte-specific Bmal1 knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including Cebpa, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte Cebpa rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (Ywhah). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.

Keywords:  Cardiometabolic disease; Circadian rhythms; Cross-tissue communication; Lipid metabolism

DOI:  https://doi.org/10.1016/j.molmet.2025.102249
Am J Physiol Cell Physiol. 2025 Sep 17.

Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice.

Brandon N VanderVeen, Thomas D Cardaci, Christian A Unger, Mitchell M NeSmith, Jeffrey C Freeman, Arianna V Bastian, Kasie Roark, Mansi Upadhyay, Andrew G Levy, Brooke M Bullard, Sierra J McDonald, Kandy T Velázquez, Reilly T Enos, Jason L Kubinak, Lorne J Hofseth, James R Hebert, Daping Fan, E Angela Murphy.

  Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ9-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Briefly, female C57BL/6 mice were randomized into four groups (n=15/group): 1) Lean, 2) Obese Placebo, 3) Obese CBD, and 4) Obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 weeks prior to a 4-week cannabis (3x/week; high CBD = ~4.2 mg/kg and high THC = ~7.3 mg/kg) intervention. Consistent with our hypothesis, obesity increased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH) both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (p<0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake. Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like pro-inflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (p<0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH. Despite the legal complexities surrounding cannabis use, these data suggest both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.

Keywords:  cannabidiol; immune cells; metabolism; obesity; Δ9-tetrahydrocannabinol

DOI:  https://doi.org/10.1152/ajpcell.00503.2025