American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Metabolic effects of medium-chain triacylglycerol consumption are preserved in obesity.","authors":"Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sara L Armour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils J Færgeman, Andreas M Fritzen, Bente Kiens","doi":"10.1152/ajpendo.00234.2024","DOIUrl":"10.1152/ajpendo.00234.2024","url":null,"abstract":"<p><p>Several health-beneficial effects are associated with intake of medium-chain triacylglycerol (MCT); however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity-and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after 8 days intake compared with intake of energy-matched triacylglycerol consisting of long-chain fatty acids (long-chain triacylglycerols, LCT) using a randomized cross-over design in lean individuals (<i>n</i> = 8) and individuals with obesity (<i>n</i> = 8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate while lowering blood glucose levels over 5 h. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after 8 days of daily supplementation. Lipidomic plasma analysis in lean individuals (<i>n</i> = 4) showed that a part of the ingested MCT bypasses the liver and enters the systemic circulation as medium-chain fatty acids (MCFAs). The findings suggest that MCFAs, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.<b>NEW & NOTEWORTHY</b> We reveal that medium-chain triacylglycerol (MCT) intake increases postprandial ketogenesis and metabolic rate and reduces plasma glucose levels in humans. Notably, these responses persist in individuals with obesity and are maintained following chronic MCT supplementation. Some medium-chain fatty acids entered the circulation, suggesting that these, together with ketone bodies, act as signaling molecules/substrates in peripheral tissues. The findings highlight health beneficial effects of dietary MCT in individuals with obesity and reveal new insights into lipid biology.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E1-E20"},"PeriodicalIF":4.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492942","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":"Higher AMPK activation in mouse oxidative compared with glycolytic muscle does not correlate with LKB1 or CaMKKβ expression.","authors":"Romain Bernasconi, Kärol Soodla, Alex Sirp, Kairit Zovo, Maria Kuhtinskaja, Tiit Lukk, Marko Vendelin, Rikke Birkedal","doi":"10.1152/ajpendo.00261.2024","DOIUrl":"10.1152/ajpendo.00261.2024","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) is an energy-sensing serine/threonine kinase involved in metabolic regulation. It is phosphorylated by the upstream liver kinase B1 (LKB1) or calcium/calmodulin-dependent kinase kinase 2 (CaMKKβ). In cultured cells, AMPK activation correlates with LKB1 activity. The phosphorylation activates AMPK, shifting metabolism toward catabolism and promoting mitogenesis. In muscles, inactivity reduces AMPK activation, shifting the phenotype of oxidative muscles toward a more glycolytic profile. Here, we compared the basal level of AMPK activation in glycolytic and oxidative muscles and analyzed whether this relates to LKB1 or CaMKKβ. Using Western blotting, we assessed AMPK expression and phosphorylation in soleus, gastrocnemius (GAST), extensor digitorum longus (EDL), and heart from C57BL6J mice. We also assessed LKB1 and CaMKKβ expression, and CaMKKβ activity in tissue homogenates. AMPK activation was higher in oxidative (soleus and heart) than in glycolytic muscles (gastrocnemius and EDL). This correlated with AMPK α1-isoform expression, but not LKB1 and CaMKKβ. LKB1 expression was sex dependent and lower in male than female muscles. CaMKKβ expression was very low in skeletal muscles and did not phosphorylate AMPK in muscle lysates. The higher AMPK activation in oxidative muscles is in line with the fact that activated AMPK maintains an oxidative phenotype. However, this could not be explained by LKB1 and CaMKKβ. These results suggest that the regulation of AMPK activation is more complex in muscle than in cultured cells. As AMPK has been proposed as a therapeutic target for several diseases, future research should consider AMPK isoform expression and localization, and energetic compartmentalization.<b>NEW & NOTEWORTHY</b> It is important to understand how AMP-activated kinase, AMPK, is regulated, as it is a potential therapeutic target for several diseases. AMPK is activated by liver kinase B1, LKB1, and calcium/calmodulin-dependent kinase kinase 2, CaMKKβ. In cultured cells, AMPK activation correlates with LKB1 expression. In contrast, we show that AMPK-activation was higher in oxidative than glycolytic muscle, without correlating with LKB1 or CaMKKβ expression. Thus, AMPK regulation is more complex in highly compartmentalized muscle cells.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E21-E33"},"PeriodicalIF":4.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738052","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":"Early exposure to a cholinergic receptor blocking agent mitigates adult obesity and protects pancreatic islet function in male rats.","authors":"Ananda Malta, Camila Cristina Ianoni Matiusso, Lucas da Silva de Lima, Tatiane Aparecida Ribeiro, Laize Peron Tófolo, Douglas Lopes Almeida, Veridiana Mota Moreira, Isabela Peixoto Martins, Audrei Pavanello, Paulo Cezar de Freitas Mathias","doi":"10.1152/ajpendo.00191.2024","DOIUrl":"10.1152/ajpendo.00191.2024","url":null,"abstract":"<p><p>We tested the hypothesis that attenuation of the circulating insulin level in rats during early life can provide sustained protection against diet-induced obesity and metabolic dysfunction in adulthood. Male Wistar rats received intraperitoneal scopolamine butylbromide (SB) during the first 12 days of suckling, whereas control rats received 0.9% saline injections. The animals were weaned on <i>day 21</i> and fed a normal chow diet. At 60 days of age, the control and SB groups were fed a normal chow diet (ND; 4.5% fat) or a high-fat diet (HF; 35% fat) until 90 days of age to induce obesity and metabolic dysfunction. Insulin secretion, food intake, and body weight were measured. Pancreatic islet function, autonomic nervous system function, and glucose homeostasis were evaluated at 90 days of age. During lactation, the plasma insulin concentration was significantly lower in the SB groups than in the control group. SB rats also exhibited reduced body weight. The HF diet resulted in obesity, glucose intolerance, insulin resistance, disruption of insulin secretion, and vagal hyperactivity in adult control rats. Remarkably, SB-treated rats fed the HF diet showed attenuated body weight and adiposity and did not develop diet-induced glucose/insulin imbalance. In addition, vagal activity and adequate pancreatic islet insulin secretion were preserved. Offspring exposed to SB during early life are provided with long-lasting protection against obesity and metabolic complications induced by an HF diet. An attenuated circulating insulin level in early life may have far-reaching consequences on metabolic programming.<b>NEW & NOTEWORTHY</b> High insulin levels during early life may lead to the late development of obesity and diabetes. We investigated whether attenuation of insulin levels by using an antimuscarinic agent could prevent diet-induced obesity and diabetes. Rats' early exposure to an antimuscarinic agent reduced insulin levels during the lactation period and promoted protection against obesity and metabolic dysfunctions. Independent of the programming mechanisms, insulin levels during early life may be a defining factor of health or diseases later in life.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E34-E43"},"PeriodicalIF":4.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612362","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":"Exploring CTRP6: a biomarker and therapeutic target in metabolic diseases.","authors":"Jeevotham Senthil Kumar, Muhammad Zubair Mehboob, Xia Lei","doi":"10.1152/ajpendo.00353.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00353.2024","url":null,"abstract":"<p><p>The rising prevalence of metabolic diseases is a significant global health concern. Beyond lifestyle management, targeting key molecules involved in metabolic regulation is essential. C1q/TNF-related protein 6 (CTRP6) is notably associated with glucose and lipid metabolism, with numerous studies highlighting its regulatory functions in metabolic diseases. This review summarizes the current knowledge on CTRP6, focusing on its gene expression profiles, protein structure, gene regulation, and role in metabolic diseases. CTRP6 is widely expressed across various tissues and features four distinct domains, with the C1q domain predicted to bind to its receptor. Notably, serum levels of CTRP6 are significantly elevated in patients with obesity and type 2 diabetes. In these conditions, adipose tissue serves as a key source of CTRP6, and its involvement in adipose tissue expansion, inflammation, and nutrient sensing has been observed in several studies. CTRP6 is also implicated in type 1 diabetes, gestational diabetes mellitus, and diabetic complications, particularly diabetic nephropathy. Although some studies have suggested that CTRP6 has protective roles in atherosclerotic cell models, myocardial infarction rat models, and ischemia/reperfusion injury mouse models, methodological issues such as unreliable antibodies and unstrict controls make it difficult to draw accurate conclusions from these studies. Patients with polycystic ovary syndrome (PCOS) exhibit elevated serum levels of CTRP6, though its direct impact on PCOS phenotypes remains unclear. In conclusion, CTRP6 emerges as a promising therapeutic target for metabolic diseases. A deeper understanding of CTRP6 will empower the scientific community to develop effective interventions to address the increasing prevalence of these diseases.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863003","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":"Hepatocyte HIF-2α Aggravates NAFLD by Inducing Ferroptosis through Increasing Extracellular Iron.","authors":"Shunkui Luo, Zhanjin Lu, Lingling Wang, Yun Li, Yingjuan Zeng, Hongyun Lu","doi":"10.1152/ajpendo.00287.2023","DOIUrl":"https://doi.org/10.1152/ajpendo.00287.2023","url":null,"abstract":"<p><p>Recent research has illuminated the pivotal role of the hypoxia-inducible factor-2α (HIF-2α) / peroxisome proliferator-activated receptor alpha (PPARα) pathway in non-alcoholic fatty liver disease (NAFLD) progression. Meanwhile, HIF-2α was reported that involved in iron regulation, and aberrant iron distribution derived liver lipogenesis. Therefore, we hypothesize that HIF-2a exacerbates fatty liver by affecting iron distribution. To substantiate this hypothesis, we utilized liver-specific HIF-2α knockout mice and the LO2 cell line with overexpressed HIF-2α. HIF-2α overexpression (OE) was induced via lentiviral infection, followed by exposure to free fatty acids (FFA) and deferoxamine (DFO). In animal experiments, hepatic HIF-2α knockout resulted in lower liver lipid levels, lower liver weight, and higher serum iron levels. Enrichment in autophagy, ferroptosis, and the PI3K-AKT pathway was demonstrated through KEGG analysis in the liver of mice. In vitro experiments showed that HIF-2α increased supernatant iron. In the HIF-2α OE group, the addition of FFA led to decreased levels of reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4) protein, along with increased lipid peroxidation (LPO), cellular lipid droplets, and triglyceride content. Impressively, DFO intervention decreased supernatant iron, reversed these changes by increasing GSH and GPX4 levels, and simultaneously reduced LPO levels, cellular lipid droplets, and triglyceride content. Additionally, the expression of proteins related to β-oxidation increased, and lipid deposition in hepatocytes improved, which may be associated with the PI3K/AKT pathway. In summary, our findings suggest that HIF-2α-mediated iron flux enhances NAFLD cell susceptibility to ferroptosis, thereby impacting lipid metabolism-related genes and contributing to lipid accumulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827115","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":"IGF-1 LR3 Does Not Promote Growth in Late Gestation Growth Restricted Fetal Sheep.","authors":"Alicia White, Jane Stremming, Stephanie R Wesolowski, Saif I Al-Juboori, Evgenia Dobrinskikh, Sean W Limesand, Laura D Brown, Paul J Rozance","doi":"10.1152/ajpendo.00259.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00259.2024","url":null,"abstract":"<p><p>Insulin-like growth factor-1 (IGF-1) and insulin are important fetal anabolic hormones. Complications of pregnancy, such as placental insufficiency, can lead to fetal growth restriction FGR) with low circulating IGF-1 and insulin concentrations and attenuated glucose-stimulated insulin secretion (GSIS), which likely contribute to neonatal glucose dysregulation. We previously demonstrated that a one-week infusion of IGF-1 LR3, an IGF-1 analog with low affinity for IGF binding proteins and high affinity for the IGF-1 receptor, at 6.6 μg·kg-1·hr^-1 into normal fetal sheep increased body weight but lowered insulin concentrations and GSIS. In this study, FGR fetal sheep received either IGF-1 LR3 treatment at 1.17 ± 0.12 μg·kg-1·hr^-1 (LR3; n=7) or vehicle (VEH; n=7) for one week. Plasma insulin, glucose, oxygen, and amino acids were measured before starting treatment and at the end of the treatment period. GSIS was measured on the final treatment day. Fetal body weights, insulin, glucose, oxygen, and GSIS were not different between groups. Amino acid concentrations decreased in LR3 (Baseline vs Final individual means comparison <i>P</i>=0.0232) but not in VEH (<i>P</i>=0.3866). In summary, a one-week IGF-1 LR3 treatment did not improve growth in FGR fetuses. Insulin concentrations and GSIS were not attenuated by IGF-1 LR3, yet circulating amino acids decreased, which could reflect increased amino acid utilization. We speculate that maintaining amino acid concentrations or raising insulin, glucose, and/or oxygen concentrations to values consistent with normally growing fetuses during IGF-1 LR3 treatment may be necessary to increase fetal growth in the setting of placental insufficiency and FGR.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826600","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":"Roux-en-Y gastric bypass alleviates kidney inflammation and improves kidney function in db/db mice by activating TLCA/TGR5 pathway.","authors":"Hongmei Lang, Jie Xiang, Xiaorong Chen, Dan Tong, Lijuan Wang, Aidi Mou, Daoyan Liu, Peng Gao, Zongshi Lu, Zhiming Zhu","doi":"10.1152/ajpendo.00248.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00248.2024","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a severe diabetic microvascular complication featured by chronic low-grade inflammation. Roux-en-Y gastric bypass (RYGB) surgery has gained importance as a safe and effective surgery to treat DKD. Bile acids are significantly changed after RYGB, which brings a series of metabolic benefits, but the relationship with the improvement of DKD is unclear. Therefore, this study performed RYGB surgery on db/db mice to observe the beneficial effects of the surgery on the kidneys, and performed bile acid targeted metabolomics analysis to explore bile acid changes. We found that RYGB significantly reduced albuminuria in db/db mice, improved renal function, reversed renal structural lesions, and attenuated podocyte injury, inflammation. Notably, bile acid metabolomic analysis revealed taurolithocholic acid (TLCA) as the most significantly altered bile acid after RYGB. Further in vitro and in vivo validation experiments revealed that TLCA supplementation improved renal function and reduced renal inflammatory damage in db/db mice. In addition, TLCA inhibited high glucose-induced inflammatory damage in MPC-5 cells, and its mechanism of action may be related to activating Takeda G protein-coupled receptor 5 (TGR5), inhibiting NF-κB phosphorylation, and thus inhibiting inflammatory response. In conclusion, RYGB may play a protective role in the kidneys of diabetic mice by activating the TLCA/TGR5 pathway.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833380","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":"Studies on cortisol, corticosterone and 17β-estradiol indicate these steroids have no role in stress or reproduction in the common octopus (<i>Octopus Vulgaris</i>).","authors":"Benjamin H Maskrey, Carolina Costas, Luís Méndez-Martínez, Laura Guerrero-Peña, Ricardo Tur, Pablo García, Pablo Touriñan, David Chavarrias, Adelino V Canario, Alex P Scott, Josep Rotllant","doi":"10.1152/ajpendo.00251.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00251.2024","url":null,"abstract":"<p><p>The common octopus (<i>Octopus vulgaris</i>) is a promising candidate for aquaculture diversification, particularly in Europe. As interest in octopus farming grows, animal welfare concerns arise. In bony vertebrates (teleosts and tetrapods), measurements of the levels of corticosterone or cortisol have been successfully used as indicators of stress and welfare. Here, it is explored whether octopuses also produce cortisol or corticosterone and, if so, whether they are released into the water in response to stress (as can be done in teleosts and amphibians). The ability of the octopus to absorb cortisol from the water is also investigated - with another steroid, the principle vertebrate estrogen, 17β-estradiol (E₂), being used as a positive uptake control. In this study, using liquid chromatography tandem mass spectrometry techniques, it was found that octopus haemolymph did not contain either cortisol, corticosterone, cortisone (a common metabolite of cortisol) or E₂. Nor were any of the corticosteroids consistently found in the water in which stressed octopuses were held. The results support the evolutionary argument that octopuses are unlikely to exhibit a stress response mediated by vertebrate-like corticosteroids. Octopus demonstrated a low ability to absorb cortisol from the water (<2% over 24h) but showed a high ability to absorb E₂ from water (92% over 24h). In this latter respect, the octopus is similar to other mollusks. The finding calls into doubt the origin of the E₂ measured in this species.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805599","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":"Enhanced quantification of α-cell suppression by hyperglycemia using a high-sensitivity glucagon assay.","authors":"Roy B Dyer, Marcello C Laurenti, Hannah E Christie, Sneha Mohan, Aoife Egan, Chiara Dalla Man, Adrian Vella","doi":"10.1152/ajpendo.00301.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00301.2024","url":null,"abstract":"<p><p>Accurate measurement of glucagon concentrations in a variety of conditions is necessary for subsequent estimation of glucagon secretion. Glucagon arises in the α-cell as a product of proglucagon processing. Modern 2-site immunoassays have overcome prior problems with glucagon measurement caused by cross-reactivity with other proglucagon-derived fragments. However, in response to hyperglycemia, glucagon concentrations can fall below the limit of quantification of commercial immunoassays. This has implications for the characterization of α-cell function in health, in prediabetes and in type 2 diabetes. An increase in the sensitivity of glucagon measurement was achieved by ethanol precipitation and concentration of sample prior to measurement. Concentrating the sample 6-fold enabled a decrease in the level of quantitation from 1.7 to 0.3 pmol/L with acceptable precision. To establish whether this enhanced high-sensitivity glucagon assay enhances the characterization of α-cell function in health and disease, we then estimated glucagon secretion rate (GSR) in 4 subjects. We subsequently used the relationship of GSR to glucose concentrations to characterize the α-cell response to glucose and demonstrate improved characterization of α-cell dysfunction <i>in vivo</i>.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798667","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 inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity.","authors":"Alice P Sowton, Lorenz M W Holzner, Fynn N Krause, Ruby Baxter, Gabriele Mocciaro, Dominika K Krzyzanska, Magdalena Minnion, Katie A O'Brien, Matthew C Harrop, Paula M Darwin, Benjamin D Thackray, Michele Vacca, Martin Feelisch, Julian L Griffin, Andrew J Murray","doi":"10.1152/ajpendo.00256.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00256.2024","url":null,"abstract":"<p><p>Inorganic nitrate (NO₃^-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the Metabolic Syndrome (MetS), type-II diabetes and metabolic dysfunction associated steatotic liver disease (MASLD). Administration of NO₃^- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS, however the impact of NO₃^- supplementation in diet-induced obesity is not well understood. Here we investigated the whole-body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat high-sucrose (HFHS) diet for up to 12-months of age, supplemented with 1 mM NaNO₃ (or NaCl) in their drinking water. HFHS-feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO₃^-. Furthermore, HFHS-fed mice supplemented with NO₃^- showed elevated levels of cardiac fibrosis, and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO₃^- did not enhance mitochondrial b-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO₃^- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS-feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798705","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}