American journal of physiology. Endocrinology and metabolism最新文献

{"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":"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":"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":3.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442768/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FURIN R81C variant: a link to type 2 diabetes via impaired enzymatic activity.","authors":"Ashraf Al Madhoun, Anwar Mohammad, Mohamed Abu-Farha, Prashantha Hebbar, Dania Haddad, Lavina Miranda, Arshad Channanath, Rasheeba Nizam, Malaika Bourashed, Rasheed Ahmad, Jehad Abubaker, Thangavel Alphonse Thanaraj, Fahd Al-Mulla","doi":"10.1152/ajpendo.00182.2024","DOIUrl":"10.1152/ajpendo.00182.2024","url":null,"abstract":"<p><p>Furin, a proprotein convertase, regulates glucose homeostasis by processing the insulin receptor (IR) precursor. Although the association of furin genetic variants with cardiac and neuronal diseases is well-established, studies investigating the association with type 2 diabetes (T2D) are scarce. This study aimed to examine the association of furin variants with T2D in an Arab cohort. In addition, it sought to elucidate the functional impact of these diabetes-associated variants on furin stability and kinetic activity. Of the 15 rare missense variants in furin identified in global genomic studies, only one, rs148110342_C > T_(R81C), was found in our study cohort, with a minor allele frequency of 2.4%. Allele-based association testing, adjusted for age, sex, and body mass index, revealed significant associations between the rs148110342 and being T2D and borderline associations with fasting plasma glucose and HbA1c levels. Enzyme kinetic studies showed that the R81C variant has higher <i>K</i>_m values, indicating lower enzymatic activity compared with wild-type furin. In silico structural modeling of the interactions between the R81C variant prodomain and the furin catalytic subunit revealed an increase in hydrogen bonding, which might explain the observed reduction in enzymatic activity. Furthermore, cell culture studies suggested that the R81C variant impairs furin's autocatalytic processing and its ability to cleave the precursor insulin receptor. A significant reduction in phosphorylation of ERK1/2 and AKT occurred in HEPG2 cells transfected with R81C variants, suggesting a downregulation of the IR signaling pathway. These findings suggest that the furin R81C variant can potentially impact insulin signaling and thereby contribute to T2D pathogenesis.<b>NEW & NOTEWORTHY</b> This study contributes novel insights into the role of furin variants in T2D risk. The rare rs148110342_C > T_(R81C) variant of furin exhibits a minor allele frequency of 2.4% in Arabs. We observed significant associations between the variant and being diabetic. The variant furin revealed lower enzyme kinetic activity, impairment of furin's autocatalytic processing, and a significant reduction in ERK1/2 and AKT phosphorylation. These findings suggest that the variant downregulates the IR signaling pathway.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E179-E189"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309360","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}

{"title":"Adipose tissue protein kinase D: regulation of signaling networks and its sex-dependent effects on metabolism.","authors":"Mark C Renton, Sean J Humphrey, Tim Connor, Sheree D Martin, Krystal Kemerer, Hilary Fernando, Christopher S Shaw, David E James, Kirsten F Howlett, Sean L McGee","doi":"10.1152/ajpendo.00391.2024","DOIUrl":"10.1152/ajpendo.00391.2024","url":null,"abstract":"<p><p>The protein kinase D (PKD) family of three highly homologous isoforms (PKD1, PKD2, and PKD3) is implicated as nutrient sensing signaling kinases that regulate the response of adipose and other tissues to the nutrient environment. However, the physiological role of adipose tissue PKD and its downstream cellular signaling targets are not well characterized. Here, we used phosphoproteomics that was performed to elucidate signaling events downstream of PKD activation in differentiated 3T3-L1 adipocytes using a triple isoform siRNA knockdown model. This revealed PKD-regulated pathways including insulin and cAMP signaling, which control metabolic responses in adipose tissue. An adipose tissue-specific and inducible dominant negative PKD (atDNPKD) mouse model that achieves functional inhibition of all three PKD isoforms was generated to assess the function of adipose PKD on whole body metabolism in vivo in both male and female mice. Insulin-stimulated suppression of lipolysis was blunted in male, but not in female, atDNPKD mice compared with control mice. Female, but not male, atDNPKD mice had higher fasting insulin but normal insulin action. Male atDNPKD mice showed greater sensitivity to the β₃-adrenergic receptor agonist CL316,243 on measures of lipolysis and energy expenditure and displayed greater fat oxidation during fasting. During refeeding, male atDNPKD mice consumed less food and took longer to regain body weight that was lost during fasting. These effects were not observed in female mice. These findings indicate that PKD provides sex-dependent fine-tuning control of cAMP signaling in adipose tissue which is important for the coordination of energy balance during fasting and refeeding. <b>NEW & NOTEWORTHY</b> The protein kinase D (PKD) family is a target for the treatment of obesity-related disorders. However, the physiological role of PKD in adipose tissue remains to be resolved. Using phosphoproteomics and an adipose tissue PKD loss-of-function mouse model, results demonstrate that PKD provides fine-tuning of metabolic signaling in adipose tissue and metabolic responses to fasting and refeeding challenges, via coordination of feeding behavior and regulation of body weight.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E67-E85"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198059","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":"Modeling hepatic glucose tracer kinetics from isotope dilution technique and deuterium metabolic imaging in postbariatric surgery and nonoperated individuals.","authors":"Alessandro Brunasso, Chiara Dalla Man, Simone Poli, Jeanine J Prompers, David Herzig, Roland Kreis, Lia Bally, Michele Schiavon","doi":"10.1152/ajpendo.00511.2024","DOIUrl":"10.1152/ajpendo.00511.2024","url":null,"abstract":"<p><p>Despite extensive research on liver metabolism, mathematical models describing hepatic glucose kinetics are currently limited due to the lack of organ-level data. Here, we propose a model of postprandial hepatic glucose kinetics exploiting liver deuterium metabolic imaging (DMI) data combined with plasma isotope dilution analysis in humans. We used data from 10 individuals who had previously undergone Roux-en-Y gastric bypass surgery (RYGB) and 10 healthy controls (HCs). The experimental setting included a labeled oral glucose tolerance test comprising 60 g of [6,6'-²H₂]-glucose in combination with liver DMI at 7 T. The hepatic glucose tracer signal was frequently quantified over 150 min, whereas peripheral plasma insulin and glucose tracer concentrations were measured in venous blood. The model was able to describe both liver and peripheral glucose tracer data well and provided estimates of postprandial glucose appearance and disposal in both the liver and the systemic circulation. The model predicted that almost all the ingested glucose had appeared in the liver in RYGB, but not in HC (89.0% vs. 64.0%, <i>P</i> = 0.008) after 150 min, whereas total hepatic disposal (RYGB = 26.4% vs. HC = 29.7%) and first-pass extraction (RYGB = 10.7% vs. HC = 11.4%) were similar between populations. The fraction of glucose eliminated in the periphery was greater in RYGB (49.9% vs. 25.3%, <i>P</i> = 0.003). Finally, no differences were observed in hepatic blood flow and GLUT2 transport rates. Although further studies are needed to validate and extend the model to include endogenous glucose production and disposal, it can be used to quantify parameters, and possibly reveal defects, of hepatic glucose handling.<b>NEW & NOTEWORTHY</b> The proposed hepatic model allows, for the first time, to describe postprandial liver glucose tracer kinetics in humans, allowing to estimate exogenous glucose appearance and disposal in the liver, as well as glucose transport and hepatic blood flow rate. The model may become a useful tool in clinical research by supporting the identification of metabolic defects at the hepatic level without requiring invasive procedures.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E102-E116"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141002","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}