bims-obesme 2024-12-29 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–12–29
eight papers selected by
Xiong Weng, University of Edinburgh

Adipocyte-derived ferroptotic signaling mitigates obesity.
Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis.
Identifying the location-dependent adipose tissue bacterial DNA signatures in obese patients that predict body weight loss.
The glial UDP-glycosyltransferase Ugt35b regulates longevity by maintaining lipid homeostasis in Drosophila.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
Regulation of bile acids and their receptor FXR in metabolic diseases.
Ovarian cancer-derived TGF-β1 induces cancer-associated adipocytes formation by activating SMAD3/TRIB3 pathway to establish pre-metastatic niche.
Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes.

Cell Metab. 2024 Dec 21. pii: S1550-4131(24)00456-X. [Epub ahead of print]

Adipocyte-derived ferroptotic signaling mitigates obesity.

Xue Wang, Qian Wu, Meijuan Zhong, Ying Chen, Yudi Wang, Xin Li, Wenxi Zhao, Chaodong Ge, Xinhui Wang, Yingying Yu, Sisi Yang, Tianyi Wang, Enjun Xie, Wanting Shi, Junxia Min, Fudi Wang.

  Ferroptosis is characterized as an iron-dependent and lipophilic form of cell death. However, it remains unclear what role ferroptosis has in adipose tissue function and activity. Here, we find a lower ferroptotic signature in the adipose tissue of individuals and mice with obesity. We further find that activation of ferroptotic signaling by a non-lethal dose of ferroptosis agonists significantly reduces lipid accumulation in primary adipocytes and high-fat diet (HFD)-fed mice. Notably, adipocyte-specific overexpression of acyl-coenzyme A synthetase long-chain family member 4 (Acsl4) or deletion of ferritin heavy chain (Fth) protects mice from HFD-induced adipose expansion and metabolic disorders via activation of ferroptotic signaling. Mechanistically, we find that 5,15-dihydroxyeicosatetraenoic acid (5,15-DiHETE) activates ferroptotic signaling, resulting in the degradation of hypoxia-inducible factor-1α (HIF1α), thereby derepressing a thermogenic program regulated by the c-Myc-peroxisome proliferator-activated receptor gamma coactivator-1 beta (Pgc1β) pathway. Our findings suggest that activating ferroptosis signaling in adipose tissues might help to prevent and treat obesity and its related metabolic disorders.

Keywords:  5,15-DiHETE; 5,15-dihydroxyeicosatetraenoic acid; ACSL4; HIF1α; acyl-coenzyme A synthetase long-chain family member 4; adipose tissue; ferritin; ferrology; ferroptosis; ferroptotic signaling; hypoxia-inducible factor-1α; iron metabolism; obesity

DOI:  https://doi.org/10.1016/j.cmet.2024.11.010
Elife. 2024 Dec 24. pii: RP100205. [Epub ahead of print]13

Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis.

Zewei Zhao, Longyun Hu, Bigui Song, Tao Jiang, Qian Wu, Jiejing Lin, Xiaoxiao Li, Yi Cai, Jin Li, Bingxiu Qian, Siqi Liu, Jilu Lang, Zhonghan Yang.

  The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. β3-adrenoceptor (β3-AR) is widely recognized as a canonical β-adrenergic G-protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of β3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G-protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown of Adgra3 resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers in mice. Conversely, Adgra3 overexpression activated the adipose thermogenic program and improved metabolic homeostasis in mice without exogenous ligand. We found that ADGRA3 facilitates the biogenesis of beige human or mouse adipocytes in vitro. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance in mice. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selective overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.

Keywords:  ADGRA3; GPCR; adipose; cell biology; hesperetin; human; mouse; obesity; thermogenesis

DOI:  https://doi.org/10.7554/eLife.100205
Gut Microbes. 2025 Dec;17(1): 2439105

Identifying the location-dependent adipose tissue bacterial DNA signatures in obese patients that predict body weight loss.

Matthieu Minty, Alberic Germain, Jiuwen Sun, Gracia Kaglan, Florence Servant, Benjamin Lelouvier, Emiri Misselis, Radu Mircea Neagoe, Menghini Rossella, Marina Cardellini, Rémy Burcelin, Massimo Federici, José Manuel Fernandez-Real, Vincent Blasco-Baque.

  Recent sets of evidence have described profiles of 16S rDNA sequences in host tissues, notably in fat pads that are significantly overrepresented and can serve as signatures of metabolic disease. However, these recent and original observations need to be further detailed and functionally defined. Here, using state-of-the-art targeted DNA sequencing and discriminant predictive approaches, we describe, from the longitudinal FLORINASH cohort of patients who underwent bariatric surgery, visceral, and subcutaneous fat pad-specific bacterial 16SrRNA signatures. The corresponding Porphyromonadaceae, Campylobacteraceae, Prevotellaceae, Actimomycetaceae, Veillonellaceae, Anaerivoracaceae, Fusobacteriaceae, and the Clostridium family XI 16SrRNA DNA segment profiles are signatures of the subcutaneous adipose depot while Pseudomonadaceae and Micrococcacecae, 16SrRNA DNA sequence profiles characterize the visceral adipose depot. In addition, we have further identified that a specific pre-bariatric surgery adipose tissue bacterial DNA signature predicts the efficacy of body weight loss in obese patients 5-10 years after the surgery. 16SrRNA signatures discriminate (ROC ~ 1) the patients who did not maintain bodyweight loss and those who did. Second, from the 16SrRNA sequences we infer potential pathways suggestive of catabolic biochemical activities that could be signatures of subcutaneous adipose depots that predict body weight loss.

Keywords:  Bariatric surgery; adipose fat pads; functional metagenomic; tissue microbiota

DOI:  https://doi.org/10.1080/19490976.2024.2439105
Cell Rep. 2024 Dec 24. pii: S2211-1247(24)01450-5. [Epub ahead of print]44(1): 115099

The glial UDP-glycosyltransferase Ugt35b regulates longevity by maintaining lipid homeostasis in Drosophila.

Lihong Sheng, Jianpeng Gao, Qingyuan Wei, Ye Gong, Zhi-Xiang Xu.

  Lipid droplets (LDs) are dynamic organelles essential for lipid storage and organismal survival. Studies have highlighted the importance of glial function in brain LD formation during aging; however, the genes and mechanisms involved remain elusive. Here, we found that Ugt35b, a member of the uridine diphosphate (UDP)-glycosyltransferases that catalyze the transfer of glycosyl groups to acceptors, is highly expressed in glia and crucial for Drosophila lifespan. By integrating multiomics data, we demonstrated that glial Ugt35b plays key roles in regulating glycerolipid and glycerophospholipid metabolism in the brain. Notably, we found that Ugt35b and Lsd-2 are co-expressed in glia and confirmed their protein interaction in vivo. Knockdown of Ugt35b significantly reduced LD formation by downregulating Lsd-2 expression, while overexpression of Lsd-2 partially rescued the shortened lifespan in glial Ugt35b RNAi flies. Our findings reveal the crucial role of glial Ugt35b in regulating LD formation to maintain brain lipid homeostasis and support Drosophila lifespan.

Keywords:  CP: Metabolism; CP: Neuroscience; Drosophila; Ugt35b; glia; lifespan; lipid droplets

DOI:  https://doi.org/10.1016/j.celrep.2024.115099
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Front Nutr. 2024 ;11 1447878

Regulation of bile acids and their receptor FXR in metabolic diseases.

Yao Li, Lulu Wang, Qing Yi, Linsong Luo, Yuxia Xiong.

  High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.

Keywords:  bile acid; farnesoid X receptor; metabolic disease; metabolize; metabolome

DOI:  https://doi.org/10.3389/fnut.2024.1447878
Cell Death Dis. 2024 Dec 24. 15(12): 930

Ovarian cancer-derived TGF-β1 induces cancer-associated adipocytes formation by activating SMAD3/TRIB3 pathway to establish pre-metastatic niche.

Tian Gao, Jibin Li, Tianyi Cheng, Xingguo Wang, Mengqing Wang, Zhiyang Xu, Yang Mu, Xianli He, Jinliang Xing, Shujuan Liu.

Ovarian cancer (OC) is prone to adipose tissue metastasis. However, the underlying molecular mechanisms remain elusive. Here, we observed that omental adipocytes were induced into cancer-associated adipocytes (CAAs) by OC-derived TGF-β1 to establish a pre-metastatic niche (PMN) through collagen and fibronectin secretion. Mechanistically, OC-derived TGF-β1 binds to adipocyte membrane receptors and thus activates intracellular signaling by SMAD3 phosphorylation. The activation of TGF-β1/SMAD3 signaling pathway dedifferentiates adipocytes into CAAs by upregulating Tribbles homolog 3 (TRIB3), which suppresses the phosphorylation of CEBPβ. Additionally, CAAs secrete collagen I, collagen VI, and fibronectin to remodel the extracellular matrix and promote the adhesion of OC cells. Pharmacological inhibition of the TGF-β1/SMAD3 pathway significantly inhibits CAAs and PMN formation, thereby reducing the OC metastatic burden. Our findings indicate that the formation of CAAs and PMN in adipose tissues facilitates OC cell implantation and blocking the TGF-β1/SMAD3 signaling pathway could prevent OC omental metastasis.

DOI: https://doi.org/10.1038/s41419-024-07311-3
bioRxiv. 2024 Dec 10. pii: 2024.12.09.626845. [Epub ahead of print]

Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes.

Melissa D Lempicki, Ryan J Garrigues, Tonya N Zeczycki, Brandon L Garcia, Thurl E Harris, Akshaya K Meher.

Glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorbing excess blood glucose, failure of which promotes hyperglycemia. Matrix metalloproteinases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, and surprisingly, it is unknown if they can directly target GLUT4 on the adipocyte surface and impair glucose absorption. We identified MMP2 as the highly active gelatinase, a class of MMP, in the gonadal WAT of high-fat diet-induced obese mice. In vitro, metabolic studies in 3T3-L1 adipocytes revealed MMP2 attenuated glucose absorption and glycolysis, which were recovered by an MMP2 inhibitor. In silico structural analysis using AlphaFold identified a putative MMP2 cleavage site on the extracellular domain of GLUT4. Further, in a substrate competition assay, a peptide mimicking the MMP2 cleavage motif on GLUT4 attenuated the cleavage of an MMP substrate by MMP2. Altogether, our results suggest a novel mechanism of impaired glucose absorption by adipocytes, which may contribute to hyperglycemia during obesity.

DOI: https://doi.org/10.1101/2024.12.09.626845