IF 7.7 1区医学

Diabetes Pub Date : 2025-02-03 DOI: 10.2337/db24-0360

Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu

{"title":"Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid","authors":"Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu","doi":"10.2337/db24-0360","DOIUrl":"https://doi.org/10.2337/db24-0360","url":null,"abstract":"Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-28 DOI: 10.2337/db24-0375

Shu Yang, Lijiao Xiong, Tingfeng Liao, Lixing Li, Yanchun Li, Lin Kang, Guangyan Yang, Zhen Liang

{"title":"Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ","authors":"Shu Yang, Lijiao Xiong, Tingfeng Liao, Lixing Li, Yanchun Li, Lin Kang, Guangyan Yang, Zhen Liang","doi":"10.2337/db24-0375","DOIUrl":"https://doi.org/10.2337/db24-0375","url":null,"abstract":"Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of Ubiquitin Specific Peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator activated receptor γ (PPARγ) plays a critical role in regulating muscle atrophy. This study investigates the role of deubiquitinase USP2 in mitigating muscle atrophy. Our findings revealed reduced USP2 expression in skeletal muscles of patients with type 2 diabetes. In mouse models of diabetes- and dexamethasone (DEX)-induced muscle atrophy, USP2 expression was downregulated in skeletal muscles. Usp2 knockout exacerbated muscle loss and functional impairment induced by diabetes or DEX. Moreover, skeletal muscle-specific Usp2 knockout further aggravated muscle loss and functional impairment induced by diabetes. Local injection of AAV-Usp2 into the gastrocnemius muscles of diabetic mice increased muscle mass, and improved skeletal muscle performance and endurance. It enhanced insulin sensitivity in diabetic mice, shown by lower fasting serum glucose and insulin levels and better glucose tolerance. Mechanistic analysis showed USP2 directly interacted with PPARγ by deubiquitinating it, stabilizing its protein levels, enhancing insulin signaling and sensitivity, and maintaining muscle mass. Loss of PPARγ abolishes the regulatory effects of USP2 on insulin sensitivity and muscle atrophy. MYOD1 activates USP2 transcription by binding to its promoter region. This study demonstrates the protective role of USP2 in mitigating muscle atrophy by stabilizing PPARγ through deubiquitination, particularly in models of diabetic and DEX-induced muscle atrophy. Targeting the USP2-PPARγ axis may offer promising therapeutic strategies for metabolic disorders and sarcopenia.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-24 DOI: 10.2337/db24-0497

Xiaomi Du, Karen Mendez-Lara, Siqi Hu, Rachel Diao, Guru Bhavimani, Ruben Hernandez, Kimberly Glass, Camila De Arruda Saldanha, Jason Flannick, Sven Heinz, Amit R. Majithia

{"title":"An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target","authors":"Xiaomi Du, Karen Mendez-Lara, Siqi Hu, Rachel Diao, Guru Bhavimani, Ruben Hernandez, Kimberly Glass, Camila De Arruda Saldanha, Jason Flannick, Sven Heinz, Amit R. Majithia","doi":"10.2337/db24-0497","DOIUrl":"https://doi.org/10.2337/db24-0497","url":null,"abstract":"PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403) that functions as an alternative translational start site. This downstream translation initiation site gives rise to a PPARγ protein isoform (M135), preferentially generated from alleles containing nonsense mutations upstream of c.A403. PPARγ M135 retains the DNA and ligand binding domains of full-length PPARγ but lacks the N-terminal AF-1 domain. Despite being truncated, PPARγ M135 shows increased transactivation of target genes, but only in the presence of agonists. Accordingly, human missense mutations disrupting AF-1 domain function actually increase agonist-induced cellular PPARγ activity compared to wild-type (WT), and carriers of these AF-1 disrupting variants are protected from metabolic syndrome. Thus, we propose the existence of PPARγ M135 as a fully functional, alternatively translated isoform that may be therapeutically generated to treat insulin resistance-related disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Homeobox C4 transcription factor promotes adipose tissue thermogenesis

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-24 DOI: 10.2337/db24-0675

Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang

{"title":"Homeobox C4 transcription factor promotes adipose tissue thermogenesis","authors":"Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang","doi":"10.2337/db24-0675","DOIUrl":"https://doi.org/10.2337/db24-0675","url":null,"abstract":"The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"61 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicle-associated miR-ERIA exerts the anti-angiogenic effect of macrophages in diabetic wound healing

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-24 DOI: 10.2337/db24-0701

Tingting Zeng, Kan Sun, Lifang Mai, Xiaosi Hong, Xiaodan He, Weijie Lin, Sifan Chen, Li Yan

{"title":"Extracellular vesicle-associated miR-ERIA exerts the anti-angiogenic effect of macrophages in diabetic wound healing","authors":"Tingting Zeng, Kan Sun, Lifang Mai, Xiaosi Hong, Xiaodan He, Weijie Lin, Sifan Chen, Li Yan","doi":"10.2337/db24-0701","DOIUrl":"https://doi.org/10.2337/db24-0701","url":null,"abstract":"Many cell types are involved in the regulation of cutaneous wound healing in diabetes. Clarifying the mechanism of cell-cell interactions is important for identifying therapeutic targets for diabetic cutaneous ulcers. The function of vascular endothelial cells in the cutaneous microenvironment is critical, and a decrease in their biological function leads directly to refractory wound healing. In this study, we aimed to study the interactions of macrophages with vascular endothelial cells and elucidate the mechanism of diabetic wound angiogenesis suppression. We found that macrophages polarized to the M1 type, inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs) by secreting extracellular vesicles after treatment with advanced glycation end products (AGEs-EVs), and contributed to wound angiogenesis and delayed wound healing in vivo. Mechanistically, we identified a novel miRNA enriched in AGEs-EVs, namely miR-ERIA, that suppress the biological function of HUVECs by targeting helicase with zinc finger 2 (HELZ2), and in vivo experiments showed that miR-ERIA suppression could promote wound angiogenesis and thus accelerate wound healing in diabetes. We found that miR-ERIA regulates diabetic wound angiogenesis by targeting HELZ2, suggesting a potential therapeutic target for diabetic foot ulcers.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"29 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A new model of experimental diabetic cardiomyopathy using combination of multiple doses of anomer-equilibrated streptozotocin and high fat diet: sex matters. 多剂量氨基平衡链脲佐菌素和高脂饮食联合治疗实验性糖尿病心肌病的新模型：性别问题

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-21 DOI: 10.2337/db24-0385

Loucia Karatzia, Fenn Cullen, Megan Young, Shing Hei Lam, Valle Morales, Katiuscia Bianchi, Sian M. Henson, Dunja Aksentijevic

{"title":"A new model of experimental diabetic cardiomyopathy using combination of multiple doses of anomer-equilibrated streptozotocin and high fat diet: sex matters.","authors":"Loucia Karatzia, Fenn Cullen, Megan Young, Shing Hei Lam, Valle Morales, Katiuscia Bianchi, Sian M. Henson, Dunja Aksentijevic","doi":"10.2337/db24-0385","DOIUrl":"https://doi.org/10.2337/db24-0385","url":null,"abstract":"Diabetes mellitus (DM) leads to a more rapid development of DM cardiomyopathy (dbCM) and progression to heart failure in women than men. Combination of high-fat diet (HFD) and freshly-injected streptozotocin (STZ) has been widely used for DM induction, however emerging data shows that anomer-equilibrated STZ produces an early onset and robust DM model. We designed a novel protocol utilising a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine DM model featuring dbCM analogous to humans. Furthermore, we examined the impact of biological sex on the evolution of cardiometabolic dysfunction in DM. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (n=109): Fresh STZ+HFD, Anomer-equilibrated STZ+HFD, HFD, Fresh STZ, Anomer-equilibrated STZ, Control diet+vehicle. Animals were characterised by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ+HFD led to induction of stable experimental murine DM characterised by impaired glucose homeostasis, cardiometabolic dysfunction and altered metabolome of liver, skeletal muscle, kidney and plasma. dbCM was more severe in female mice including systolic dysfunction and reduced cardiac energy reserve. This study established a novel, robust model of inducible murine DM and emphasised the impact of biological sex on DM progression and severity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"38 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic Insights Into the Exercise-Induced Changes in Muscle Lipids and Insulin Sensitivity—Expanding on the “Athlete’s Paradox”: Revisiting a 2011 Diabetes Classic by Amati et al. 对运动引起的肌脂和胰岛素敏感性变化的机制见解——对“运动员悖论”的扩展：重新审视2011年Amati等人的糖尿病经典。

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-21 DOI: 10.2337/dbi24-0030

Jeffrey F. Horowitz, Bret H. Goodpaster

引用次数: 0

Novel T Cell reactivities to Hybrid Insulin Peptides in Islet Autoantibody-Positive At-Risk Subjects 胰岛自身抗体阳性高危人群中新型T细胞对混合型胰岛素肽的反应

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-16 DOI: 10.2337/db24-0611

Anita C. Hohenstein, Joylynn Gallegos, Mylinh Dang, Jason Groegler, Hali Broncucia, Fatima Tensun, Kathleen Waugh, Fran Dong, Eddie A. James, Cate Speake, Andrea K. Steck, Marian J. Rewers, Peter A. Gottlieb, Kathryn Haskins, Thomas Delong, Rocky L. Baker

{"title":"Novel T Cell reactivities to Hybrid Insulin Peptides in Islet Autoantibody-Positive At-Risk Subjects","authors":"Anita C. Hohenstein, Joylynn Gallegos, Mylinh Dang, Jason Groegler, Hali Broncucia, Fatima Tensun, Kathleen Waugh, Fran Dong, Eddie A. James, Cate Speake, Andrea K. Steck, Marian J. Rewers, Peter A. Gottlieb, Kathryn Haskins, Thomas Delong, Rocky L. Baker","doi":"10.2337/db24-0611","DOIUrl":"https://doi.org/10.2337/db24-0611","url":null,"abstract":"Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in T cell-mediated beta-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins. To identify T cell specificities contributing to T1D pathogenesis, we tested T cell reactivity from T1D patients or healthy control using an IFN-γ ELISPOT assay against a library of 240 C-peptide HIPs. We observed elevated T cell responses to peptide pools containing HIPs that form at the amino acid residues G15, A18 and L26 of C-peptide. In a second cohort of healthy controls, at-risk individuals, and T1D patients, T cell reactivity to HIPs forming at these three residues was monitored. Results indicate that, prior to clinical onset of T1D, there were significantly elevated responses to multiple pools of HIPs, and the magnitude of T cell reactivity to HIPs forming at residue A18 of the C-peptide was increased. Overall, our study identifies new T cell specificities in at-risk subjects and indicates that T cell reactivity to HIPs can be observed before T1D onset.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3D Imaging Resolves Human Pancreatic Duct-β-Cell Clusters During Cystic Change 三维成像解析囊变过程中人类胰管β细胞簇

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-09 DOI: 10.2337/db24-0824

Chih-Yuan Lee, Ting-Chun Kuo, Ya-Hsien Chou, Shih-Jung Peng, Fu-Ting Hsiao, Mei-Hsin Chung, Li-Wen Lo, Chia-Ning Shen, Hung-Jen Chien, Hsiu-Pi Chang, Chien-Chia Chen, Yung-Ming Jeng, Yu-Wen Tien, Shiue-Cheng Tang

{"title":"3D Imaging Resolves Human Pancreatic Duct-β-Cell Clusters During Cystic Change","authors":"Chih-Yuan Lee, Ting-Chun Kuo, Ya-Hsien Chou, Shih-Jung Peng, Fu-Ting Hsiao, Mei-Hsin Chung, Li-Wen Lo, Chia-Ning Shen, Hung-Jen Chien, Hsiu-Pi Chang, Chien-Chia Chen, Yung-Ming Jeng, Yu-Wen Tien, Shiue-Cheng Tang","doi":"10.2337/db24-0824","DOIUrl":"https://doi.org/10.2337/db24-0824","url":null,"abstract":"Pancreatic cystic changes in adults are increasingly identified through advanced cross-sectional imaging. However, the impact of initial/intra-lobular epithelial remodeling on the local β-cell population remains unclear. In this study, we examined 10 human cadaveric donor pancreases (tail and body regions) via integration of stereomicroscopy, clinical H&E histology, and 3D immunohistochemistry, identifying 36 microcysts (size: 1.22±0.56 mm) alongside 54 low-grade pancreatic intraepithelial neoplasias (positive control of epithelial remodeling; size: 2.42±1.05 mm). Both conditions exhibited significant increases in CK7 and insulin immunoreactive signals compared with normal lobules. Importantly, despite luminal contents of microcysts causing false positives (autofluorescence) in fluorescence imaging, the defined cystic epithelium showed distinct duct-β-cell associations—including β-cells in the epithelium and duct-β-cell clusters—visualized via antifade 3D/Airyscan super-resolution imaging in the high-refractive-index polymer. The peri-luminal β-cells displayed insulin+ vesicles residing near the basal domain, while the CK7+ cytokeratins in duct cells accumulated in the apical domain, underlining polarized tissue and cellular organizations. Overall, in microcyst formation, we demonstrate local and associated pancreatic exocrine and endocrine tissue remodeling. Because artifacts are a concern in β-cell investigation in a novel environment, our work using 3D-labeled human pancreas with cytokeratin and vesicle resolving powers provides a robust approach for characterizing the duct-β-cell association in a clinically relevant setting.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Time-resolved effects of short-term overfeeding on energy balance in mice 短期过量进食对小鼠能量平衡的时间分辨效应

IF 7.7 1区医学

Diabetes Pub Date : 2025-01-09 DOI: 10.2337/db24-0289

Pablo Ranea-Robles, Camilla Lund, Charlotte Svendsen, Cláudia Gil, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen

{"title":"Time-resolved effects of short-term overfeeding on energy balance in mice","authors":"Pablo Ranea-Robles, Camilla Lund, Charlotte Svendsen, Cláudia Gil, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen","doi":"10.2337/db24-0289","DOIUrl":"https://doi.org/10.2337/db24-0289","url":null,"abstract":"To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion. Furthermore, to assess the role of adipose tissue thermogenesis in protecting against overfeeding-induced weight gain, we analyze the expression of genes involved in futile metabolic cycles in response to overfeeding and subject uncoupling protein 1 (UCP1) knockout (KO) mice to intragastric overfeeding. Data from two independent experiments demonstrate that 7 days of 140-150% overfeeding results in substantial weight gain and triggers a potent, sustained decrease in voluntary food intake, which coincides with a gradual return of body weight toward baseline after overfeeding. Intragastric overfeeding triggers an increase in energy expenditure that seems to be adaptive. However, mice lacking UCP1 are not impaired in their ability to defend against overfeeding-induced weight gain. Finally, we show that fecal energy excretion decreases in response to overfeeding, but only during the recovery period, driven primarily by a reduction in fecal output rather than in fecal caloric density. In conclusion, while overfeeding may induce adaptive thermogenesis, the primary protective response to forced weight gain in mice appears to be a potent reduction in food intake.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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