American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Maladaptive trained immunity of adipose tissue macrophages unraveling the link to obesity, T2DM, and beyond.","authors":"Siyi Chen, Jiayao Fu, Jiayu Yan, Ruowen Zhao, Chunhua Qian, Zulalai Yisimayili, Junhua Wu","doi":"10.1152/ajpendo.00071.2025","DOIUrl":"10.1152/ajpendo.00071.2025","url":null,"abstract":"<p><p>Maladaptive trained immunity and associated chronic low-grade inflammation contribute to metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and cardiometabolic disorders. The heterogeneity and plasticity of adipose tissue macrophages (ATMs) are essential for preserving adipose tissue (AT) homeostasis. The obese AT microenvironment trains ATMs to undergo adaptive changes, especially transition to a maladaptive state, and exacerbates the inflammation associated with obesity and T2DM. This review focuses on the pivotal role of ATMs in propagating local inflammation from AT to distant organs, a process that is central to the systemic effects of obesity. In addition, we emphasize the potential of targeted therapeutic interventions that leverage the axes of maladaptive trained immunity. The advancement of interleukin-1β and NLR family pyrin domain containing 3 targeted agents represents an innovative and promising research frontier, with the potential to transform immunotherapy for metabolic disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E117-E130"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermogenesis and reduced lipid synthesis: one-anastomosis gastric bypass bariatric surgery 6-mo follow-ups in adipose tissue health context for type 2 diabetes.","authors":"Iurii Stafeev, Margarita Agareva, Svetlana Michurina, Alina Tomilova, Ekaterina Shestakova, Anastasiya Voznesenskaya, Maria Sineokaya, Natalia Alekseeva, Maria Boldyreva, Elizaveta Ratner, Yelena Parfyonova, Marina Shestakova","doi":"10.1152/ajpendo.00033.2025","DOIUrl":"10.1152/ajpendo.00033.2025","url":null,"abstract":"<p><p>One-anastomosis gastric bypass (OAGB) represents a novel less invasive bariatric surgery technique that can significantly improve systemic metabolism and adipose tissue health in patients with type 2 diabetes mellitus (T2DM). Previously, we demonstrated that T2DM impairs proliferation and differentiation of adipose tissue progenitors. Obese patients with T2DM (<i>n</i> = 10) underwent clinical examination and subcutaneous fat biopsy during bariatric surgery and in 6 mo. Adipose-derived stem cells (ADSCs) were isolated by enzymatic method. Cell proliferation was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and immunocytochemistry. Adipogenesis and thermogenesis were assessed by confocal microscopy. Adipocyte metabolism was estimated by radioisotope tracing. Western blotting was used to quantify protein expression. Median weight loss after OAGB was 40 kg. OAGB resolved hyperinsulinemia and stimulated insulin sensitivity with changes in homeostatic model assessment of insulin resistance and M-index up to twofold. Bariatric surgery significantly influenced properties of ADSC adipocytes: there were an increase in ADSC proliferation, decrease in white adipogenesis, activation of white and beige adipocyte lipid droplet fragmentation, activation of thermogenesis, and inhibition of lipogenesis. OAGB promotes weight loss and insulin sensitivity and changes regenerative potential of ADSC. Enhanced ability of ADSC to proliferate and differentiate into thermogenic adipocytes with reduced activity of lipogenesis may prevent weight gain after bariatric surgery.<b>NEW & NOTEWORTHY</b> Today, bariatric surgery remains the most effective instrument for weight loss, glycemic control, and type 2 diabetes combat. Bariatric surgery causes mild stimulation of ADSC proliferation and suppresses white adipogenesis. ADSC-derived adipocytes exhibited lipid droplet fragmentation, activation of thermogenesis, and inhibition of lipogenesis. Thus, enhanced ability of ADSC to proliferate and differentiate into thermogenic adipocytes with reduced activity of lipogenesis may support energy expenditure and prevent weight gain after bariatric surgery.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E86-E101"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing measures of insulin-regulated lipolysis in humans.","authors":"Yilin Song, Kelli A Lytle, Michael D Jensen","doi":"10.1152/ajpendo.00078.2025","DOIUrl":"10.1152/ajpendo.00078.2025","url":null,"abstract":"<p><p>The goals of these studies were to test for errors in measuring the insulin concentration resulting in 50% suppression from baseline free fatty acid palmitate rate of appearance (FFA_palmitate IC₅₀) when measured with a two-step, euglycemic, hyperinsulinemic clamp (EHC). We also determined the reproducibility of FFA_palmitate IC₅₀ in weight-stable adults and assessed the magnitude of the change in FFA_palmitate IC₅₀ in response to weight loss. To accomplish this, we analyzed data from 46 studies of 27 volunteers enrolled in two ongoing clinical research studies that included weight loss by lifestyle intervention or bariatric surgery. FFA palmitate kinetics were measured using an intravenous infusion of [U-¹³C]palmitate under basal (fasting) and a two-step EHC. For 40 of 46 studies, calculating FFA_palmitate IC₅₀ using data from both steps of a EHC overestimated FFA_palmitate IC₅₀ compared with the first (low) dose, which suppressed palmitate Ra by > 50%. FFA_palmitate IC₅₀ did not change and was reproducible after 4 mo (<i>r</i> = 0.70, <i>P</i> = 0.02) for 10 weight-stable volunteers. Weight loss by either intervention reduced FFA_palmitate IC₅₀, and the reduction was correlated with fat loss and change in adipocyte size. We conclude that, although a two-step EHC (with an initial low dose) allows accurate assessment of FFA_palmitate IC₅₀, careful scrutiny of each set of study data is needed. These data will improve the ability of investigators to design studies that can detect small but important differences or changes in adipose tissue insulin action. NCT clinical trial numbers NCT03866408 and NCT03868592.<b>NEW & NOTEWORTHY</b> Accurate measures of insulin regulation of adipose tissue lipolysis (free fatty acid release rates) in humans can be accomplished using a two-step, hyperinsulinemic clamp experimental design, but careful scrutiny of the data is needed. The FFA_palmitate IC₅₀ measure is reproducible in weight-stable adults and responds to treatment interventions in a quantitative manner.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E59-E66"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut lactate increases circulating l-Lac-Phe and key metabolites linked to GLP-1 and human health.","authors":"Emaan Ghias, Mette Glavind Bülow Pedersen, Camilla Bak Nielsen, Louise Vase Bech, Ida Marie Modvig, Natasa Brkovic Zubanovic, Jacob Marthinsen Seefeldt, Roni R Nielsen, Esben Søndergaard, Kim Frisch, Jakob Hansen, Jens Juul Holst, Niels Møller, Nikolaj Rittig, Mogens Johannsen","doi":"10.1152/ajpendo.00037.2025","DOIUrl":"10.1152/ajpendo.00037.2025","url":null,"abstract":"<p><p>Lactate, a small organic acid related to short-chain fatty acids, is emerging as a key energy metabolite, although much remains unknown about its actions in the gut. In the current study, we specifically tested how oral and parenteral (IV) lactate affects lactoylation of amino acids in humans and whether these clinical results could be reproduced in a perfused rat intestine model. Furthermore, using targeted and untargeted metabolomics, we globally investigated how oral and IV lactate impacts the circulating metabolome to delineate potential circulating messengers and obtain additional mechanistic insights into how oral lactate may potentially induce glucagon-like peptide-1 secretion as well as alternative metabolites correlated to human health. Our findings provide a better understanding of the general effects of lactate in the gut and how it potentially signals to increase satiety in humans.<b>NEW & NOTEWORTHY</b> By investigating the effects of oral versus IV lactate administration, we find that oral lactate elevates plasma l-lactate and strongly increases circulating l-Lac-Phe and l-Lac-Val, potentially via an alternative mechanism than exercise-induced formation. Furthermore, we find that GLP-1 secretion is not directly induced by lactate but may be mediated via increased bile acids and SCFAs in the gut.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E143-E150"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel tools for studying the fish growth hormone axis in vivo.","authors":"Genevieve L Fernandes, Deodatta S Gajbhiye, Yaara Y Columbus-Shenkar, Matan Golan","doi":"10.1152/ajpendo.00471.2024","DOIUrl":"10.1152/ajpendo.00471.2024","url":null,"abstract":"<p><p>Growth hormone (Gh) is the main regulator of fish growth, making it vital to understand how Gh is controlled. However, studying Gh regulation has been limited by the lack of suitable fish models. We identified conserved regulatory elements in tilapia <i>gh</i> and cloned a functional promoter. By using this promoter, we generated reporter transgenic fish lines of zebrafish and tilapia with labeled somatotrophs. Our in vitro and in vivo investigation revealed that the first intron of the tilapia <i>gh</i> contains functional enhancer elements crucial for transgene expression. Tilapia transgenic lines expressing the calcium-sensitive protein GCaMP6s allow the visualization of calcium activity in somatotrophs within intact pituitary glands. Network plots derived from the cell coactivation revealed distinct patterns of activity, showing cell groups with synchronized behavior, suggesting the presence of functional clusters within the somatotroph population. Furthermore, our zebrafish reporter lines revealed higher spontaneous calcium activity of Gh cells in juveniles compared with adults, suggesting increased somatotroph activity in rapidly growing young fish. Overall, our study demonstrates the functionality of tilapia and zebrafish Gh transgenic lines for investigating Gh cell activity in vivo. Combined with previously established methodologies, these transgenic lines serve as valuable tools for studying the regulation and release of Gh in the largest group of living vertebrates.<b>NEW & NOTEWORTHY</b> This study describes the first transgenic reporter tools for real-time imaging of calcium activity and reporter gene expression in fish growth hormone cells. By identifying critical enhancer elements in <i>gh</i>, we successfully targeted somatotroph cells and performed functional analysis of their behavior within the physiological context. These tools could provide valuable insights into growth hormone (Gh) regulation, with important implications in aquaculture and our understanding of the evolution of vertebrate endocrine systems.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E131-E142"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic succinate exposure does not cause liver injury.","authors":"Joseph Balnis, Emily L Jackson, Lisa A Drake, Catherine E Vincent, Hwajeong Lee, Harold A Singer, Ariel Jaitovich","doi":"10.1152/ajpendo.00129.2025","DOIUrl":"10.1152/ajpendo.00129.2025","url":null,"abstract":"<p><p>Patients with metabolic syndrome and liver dysfunction demonstrate elevated levels of succinate in the circulation. Succinate has been causally associated with nonalcoholic fatty liver disease (NAFLD) in multiple animal models and via different mechanisms including interaction with succinate receptor-1 (SUCNR-1) in hepatic stellate cells (HSCs), activity of AMP-activated protein kinase (AMPK) and others. Although skeletal muscle is a major source of endogenous succinate, here, using a transgenic mouse with muscle-specific ablation of succinate dehydrogenase complex subunit C (SDHC knockout animal), we show that sustained, long-term endogenous elevation of blood succinate does not cause liver injury. Both macroscopically and histologically, livers from transgenic animals appear similar to wild-type counterparts. Moreover, tests for liver function and other biochemical serum surrogates of organ integrity, and measurements of oxygen consumption by high resolution respirometry, do not indicate evidence of succinate-induced liver toxicity in transgenic animals. This data suggests that chronically elevated endogenous succinate causes no conspicuous evidence of liver dysfunction at histological, biochemical, or metabolic levels.<b>NEW & NOTEWORTHY</b> Succinate has been associated with hepatotoxicity in cellular, animal, and human models, including metabolic syndrome. This is the first report that evaluates the liver integrity effect of chronically elevated systemic succinate as measured by mass spectrometry. We show that liver histopathology, functional readouts, and high-resolution respirometry show normal levels following chronic succinate exposure. Thus, this research challenges the prevalent concept that succinate elevation is injurious to the liver in vivo.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E39-E45"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice.","authors":"Joke Seuntjens, Jente De Gols, Bethan K Davies, Fien Van Looy, Ingrid Stockmans, Karen Moermans, Geert Carmeliet, Christophe Matthys, Roman Vangoitsenhoven, Bart Van Der Schueren, Steve Stegen, Mitsugu Shimobayashi","doi":"10.1152/ajpendo.00010.2025","DOIUrl":"10.1152/ajpendo.00010.2025","url":null,"abstract":"<p><p>Obesity is associated with the development of type 2 diabetes. In recent years, incretin analogs have been prescribed at a high rate for the treatment of obesity and diabetes due to their potent effects on lowering body weight and improving glucose homeostasis. However, many patients do not stay on incretin analog therapy and thereby rapidly regain body weight. The noncompliance of patients to incretin analog therapy is not only due to drug shortage but also insufficient knowledge of the long-term effects of the therapy. To address this knowledge gap, we examined the effects of incretin analog treatment and withdrawal on adipose tissue functions in high-fat diet (HFD)-induced obese mice. Our transcriptome data suggest that incretin analog treatment restored most of obesity-mediated deregulated gene expression in adipose tissue. However, genes encoding lipogenic enzymes, downregulated by HFD, were not restored by incretin analog treatment. Interestingly, a dietary intervention with normal chow diet (ND) feeding, but not calorie-matched HFD feeding, restored the expression of lipogenic enzymes. Upon incretin analog therapy withdrawal, mice displayed rapid body weight regain, impaired adipose tissue function, and glucose intolerance. In contrast, an ND intervention following incretin analog therapy withdrawal restored lipogenic gene expression in adipose tissue, maintained glucose homeostasis, and minimized body weight regain. This study revealed the effects of incretin analog therapy and therapy withdrawal on adipose tissue and highlights the importance of the dietary composition during and after incretin analog therapy. Thus, our findings may contribute to the development of long-term therapy guidelines of incretin analog therapy for patients with obesity.<b>NEW & NOTEWORTHY</b> A dietary intervention following incretin analog treatment restores adipose tissue function and maintains body weight and glucose homeostasis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E46-E58"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut hormone secretion in a new meal tolerance test on insulin, glucagon, and glycemic excursions in patients with morbid obesity undergone sleeve gastrectomy.","authors":"Yukako Yamamoto, Masaki Kobayashi, Takeshi Togawa, Osamu Sekine, Yuki Ozamoto, Junko Fuse, Jun Ito-Kobayashi, Yasumitsu Oe, Akeo Hagiwara, Masanori Iwanishi, Akira Shimatsu, Tadahiro Kitamura, Atsunori Kashiwagi","doi":"10.1152/ajpendo.00492.2024","DOIUrl":"10.1152/ajpendo.00492.2024","url":null,"abstract":"<p><p>We have reported that hypoglycemia during a 75-g oral glucose tolerance test (OGTT) in patients who underwent a laparoscopic sleeve gastrectomy (LSG) is prevented by a new mixed meal tolerance test (MTT) containing lipid, protein, and carbohydrate equivalent to 75-g glucose. We investigated whether the secretions of gut hormones, including glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glicentin during OGTT, were involved in reactive hypoglycemia observed in post-LSG patients through changes in plasma insulin and glucagon secretions. Thus, we compared these gut hormone secretions during the OGTT and MTT in 30 Japanese patients pre- and 1-yr post-LSG. Both GLP-1 and glicentin secretions were glucose-dependently stimulated in pre-LSG patients and were enhanced by the LSG. This enhancement was associated with postprandial hypoglycemia through both enhanced acute insulin secretion and suppressed glucagon secretion during the OGTT in the post-LSG patients whose calculated disposition index improved. Conversely, the MTT in the post-LSG patients attenuated the insulin secretion and enhanced both GIP and glucagon secretions, resulting in protection of hypoglycemia. The GIP secretion was stimulated during the OGTT without association with insulin secretion, and the baseline GIP levels were positively correlated with HOMA-R in both pre- and post-LSG patients. In conclusion, the glucose-induced glicentin and GLP-1 secretions were associated with glucose-induced postprandial hypoglycemia through an overstimulation of acute insulin secretion in post-LSG patients. The new MTT is useful to evaluate normalization of glucose tolerance through attenuation of glucose-stimulated glicentin and GLP-1 secretions and enhanced GIP and glucagon secretions in post-LSG patients.<b>NEW & NOTEWORTHY</b> In postlaparoscopic sleeve gastrectomy (LSG) patients with enhanced disposition index, the standard OGTT resulted in postprandial reactive hypoglycemia, precluding accurate assessment of glucose tolerance. Glucose-induced glicentin and GLP-1 secretions were implicated in this phenomenon. However, a mixed meal test using 75-g carbohydrate, fat, and protein attenuated such reactive hypoglycemia, providing an accurate assessment of glucose tolerance through attenuation of both glicentin and GLP-1 oversecretions and enhanced GIP and glucagon secretions in post-LSG patients.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E25-E38"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptin in the VMH contributes to the initial overconsumption of palatable diets by rats.","authors":"Emily E Noble, Ruth B S Harris","doi":"10.1152/ajpendo.00090.2025","DOIUrl":"10.1152/ajpendo.00090.2025","url":null,"abstract":"<p><p>Deleting leptin receptors from VMH steroidogenic factor 1-expressing neurons exaggerates diet-induced obesity in mice. Experiments described here tested whether VMH leptin receptors prevent obesity in rats. Male, but not female, Sprague-Dawley rats increased energy intake for 3 days when offered a 45% kcal fat high-fat (HF) diet. There was no change in body composition of either sex during 60 days of HF feeding. Basal leptin signaling was not changed during overeating, but hindbrain leptin activity was downregulated when HF-fed rats corrected energy intake. Male and female rats exhibited increased sensitivity to VMH leptin only during the early days of being offered an HF diet. Deletion of VMH leptin receptor-expressing cells using leptin-saporin (Lep-Sap) prevented the initial hyperphagia in males but did not change subsequent energy intake, expenditure, adiposity, or glucose clearance compared with rats fed a 10% kcal fat diet. Surprisingly, HF-fed Lep-Sap rats responded to peripheral injection of leptin, whereas LF-fed Lep-Sap rats did not. Male Lep-Sap rats showed increased preference for a 2% sucrose solution but were more accurate than control blank-Sap rats in compensating for consumption of a 10% sucrose solution. Similarly, Lep-Sap rats offered a choice diet of lard, 30% sucrose, and chow increased energy intake and body fat mass but consumed less than blank-Sap rats during the first 4 days on the diet by decreasing chow intake. These results suggest that VMH leptin receptors in rats contribute to the early overconsumption of palatable diets and that this is reversed when leptin signaling in the nucleus tractus solitarius and VMH is downregulated.<b>NEW & NOTEWORTHY</b> When rats are offered a high-fat diet, they overeat for the first few days, and then energy intake decreases to a lower, stable level. Experiments described here demonstrate that leptin receptors in the ventromedial hypothalamus of rats are required for this overeating. Loss of these receptors appears to result in an increased preference for sucrose solution but a greater precision of the control of energy intake.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E1-E17"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC1 deacetylates PGC-1α and its inhibition improves glucose homeostasis in diet-induced obese mice.","authors":"Chaim Atay Fainshtein, Or Maalumi, Keren-El De-Leon, Rachel Barkan-Michaeli, Kfir Sharabi","doi":"10.1152/ajpendo.00399.2024","DOIUrl":"10.1152/ajpendo.00399.2024","url":null,"abstract":"<p><p>Excessive hepatic glucose production (HGP) driven by increased gluconeogenesis is a hallmark of type 2 diabetes, making its inhibition a crucial strategy for reducing hyperglycemia. Central to HGP regulation is the transcriptional coactivator proliferator-activated receptor gamma coactivator 1α (PGC-1α), which promotes the expression of key gluconeogenic enzymes. The acetylation state of PGC-1α significantly influences its coactivating potential, with increased acetylation-whether induced genetically or chemically-shown to suppress its gluconeogenic activity and lower hyperglycemia. The delicate balance between specific acetyltransferases and deacetylases determines the acetylation status of PGC-1α and, consequently, its activity. Although the role of sirtuin deacetylases in PGC-1α acetylation has been extensively studied, zinc-dependent histone deacetylases (HDACs) have received less attention in this context. In this study, we demonstrate that HDAC1 strongly deacetylates PGC-1α, enhancing its ability to coactivate the transcription factor hepatic nuclear factor 4α. Furthermore, we show that depleting <i>Hdac1</i> in mouse primary hepatocytes and liver tissue reduces glucose production, consistent with decreased PGC-1α activity. Although the HDAC family has been investigated for their contributions to metabolic homeostasis, our findings reveal a specific mechanistic pathway by which HDAC1 modulates glucose homeostasis.<b>NEW & NOTEWORTHY</b> We identify HDAC1 as a regulator of PGC-1α acetylation and gluconeogenic activity in hepatocytes. Genetic depletion of HDAC1 increases PGC-1α acetylation in hepatocytes and reduces hepatic glucose production, revealing a previously unrecognized mechanism for glucose homeostasis. These findings highlight HDAC1 as a potential therapeutic target for type 2 diabetes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E151-E159"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}