American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Topical application of menthol enhances brown adipose tissue thermogenesis and fat oxidation in humans.","authors":"Hitoshi Wakabayashi, Tomomi Fujimoto, Aiko Miura, Juno Kita, Mami Matsushita, Toshimitsu Kameya, Takafumi Maeda, Masayuki Saito","doi":"10.1152/ajpendo.00243.2025","DOIUrl":"10.1152/ajpendo.00243.2025","url":null,"abstract":"<p><p>This study examined the relationship between human brown adipose tissue (BAT) activity and thermogenesis in response to topical menthol application, which activates the transient receptor potential melastatin-8 in individuals with various BAT activity. Thirteen healthy male participants were separated into high (<i>n</i> = 6) and low (<i>n</i> = 7) BAT groups based on BAT activity (SUV_max). They were placed in a supine position at 27°C for 120 min with 4% l-menthol or a control solution applied to their abdomen and lower limbs. Expired gas was measured to calculate energy expenditure (EE) and substrate oxidation. Menthol application increased EE at 60-120 min, with no effect in the controls. Changes in EE adjusted for free fat mass (ΔEE/FFM) were significantly higher following menthol treatment compared with the control application at 60-120 min in the high BAT group (<i>P</i> < 0.05), but not in the low BAT group. A significant positive correlation was observed between SUV_max and EE/FFM averaged over 60-120 min with menthol treatment (<i>r</i> = 0.57, <i>P</i> < 0.05), but not in the controls. Fat oxidation averaged over 60-120 min was significantly greater with menthol in the high BAT group (<i>P</i> < 0.05) compared with the low BAT group. Rectal temperature at 120 min was significantly higher with menthol treatment in the high BAT groups (<i>P</i> < 0.05); however, menthol showed a minor effect on vasomotor responses, with no effect from BAT activity. Taken together, topical menthol application enhances thermogenesis and fat oxidation, which depends, in part, on BAT activity.<b>NEW & NOTEWORTHY</b> This study examined the relationship between human brown adipose tissue (BAT) activity and thermogenesis in response to topical menthol application, which activates transient receptor potential melastatin-8. A significant positive correlation was observed between BAT activity and energy expenditure. Fat oxidation was significantly greater with menthol application in the individuals with high BAT activity. Taken together, topical menthol application enhances thermogenesis and fat oxidation, which depends, in part, on BAT activity in humans.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E302-E311"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599124","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":"Exendin-4 induced retching-like behavior mediated by postsynaptic effect via AMPA receptors in the area postrema of mice.","authors":"Hanting Ding, Mengtian Wang, Jian Zhang, Chenchen Wan, Zhaohuan Huang, Ling Liu, Ji Liu","doi":"10.1152/ajpendo.00174.2025","DOIUrl":"10.1152/ajpendo.00174.2025","url":null,"abstract":"<p><p>Although glucagon-like peptide-1 (GLP-1) analogs have been clinically approved for type 2 diabetes mellitus (T2DM) and obesity treatment for an extended period, their associated adverse effects of nausea and vomiting remain unsolved. To elucidate the neural mechanisms underlying GLP-1-induced emesis, we investigated how GLP-1 signaling in the area postrema (AP) modulates retching-like behavior in mice. Our experiments demonstrated that intraperitoneal administration of the GLP-1 receptor agonist Exendin-4 (Exn4) induced dose-dependent retching-like behavior, which was replicated by direct Exn4 administration into the AP. Notably, while vagal afferent denervation failed to attenuate Exn4-induced retching-like behavior, genetic ablation of GLP-1 receptor (GLP-1R) expression in the AP completely abolished this response, establishing AP GLP-1R as the critical mediator of GLP-1-associated emesis. Further mechanistic studies revealed that Exn4 enhances AP GLP-1R neuronal activity through a postsynaptic pathway dependent on AMPA receptor signaling. These findings provide a neural circuit basis for GLP-1-induced emesis and identify a potential therapeutic target for mitigating this clinically significant side effect.<b>NEW & NOTEWORTHY</b> Here, we used a mouse-based paradigm to identify that the retching-like behavioral effects are caused by direct central GLP-1R neurons activation in the caudal brainstem, independent of the vagal afferent pathway. Importantly, the activation of AP^GLP-1R is mediated by postsynaptic AMPA receptors, which strengthen excitatory currents. Thus, we revealed the target and neural basis of GLP-1 analog-induced vomiting effect, which highlights a potential intervening site for clinical treatment.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E254-E265"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582832","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":"Intestinal KLHL12 is dispensable for lipid absorption and chylomicron metabolism.","authors":"Zhiming Zhao, Wei Lu, Changwei Li, Meixi Xu, Bo Wang","doi":"10.1152/ajpendo.00219.2025","DOIUrl":"10.1152/ajpendo.00219.2025","url":null,"abstract":"<p><p>Kelch-like protein 12 (KLHL12) has been shown to regulate coat complex II (COPII)-mediated endoplasmic reticulum (ER)-to-Golgi trafficking of large cargos carrying procollagen or apolipoprotein B-100 containing very-low-density lipoprotein (VLDL). It is known that lipid absorption and chylomicron metabolism in enterocytes are dependent on apolipoprotein B-48 (ApoB48) and COPII-mediated trafficking. This study aimed to investigate whether KLHL12 in the intestine regulates dietary lipid absorption, chylomicron assembly, and metabolic phenotypes in mice. We generated <i>Klhl12</i> intestinal-specific knockout (IKO) mice and assessed the impact of its deficiency on lipid absorption and Western diet (WD)-induced obesity in both male and female mice. We examined lipid absorption in vivo by acute oil gavage and fasting/high-fat diet (HFD) refeeding. Under chow diet feeding and fasting/HFD-refeeding conditions, <i>Klhl12</i> IKO mice showed no significant changes in serum lipid levels compared with controls. Although Western blot analysis revealed increased ApoB48 in the intestine, no differences in serum ApoB were detected. Similarly, IKO mice on a 12-wk WD exhibited comparable body weight gain and similar serum lipid profiles with those of control mice. Our findings demonstrate that the deletion of intestinal <i>Klhl12</i> does not significantly alter systemic lipid levels or body weight under different dietary challenges, suggesting that KLHL12 is not required for lipid absorption and chylomicron metabolism.<b>NEW & NOTEWORTHY</b> KLHL12 has been reported to regulate the trafficking of large COPII vesicles from the ER to the Golgi, including VLDL secretion in the hepatoma cells. Lipid absorption in the intestine involves COPII-mediated trafficking of chylomicron in enterocytes. In this study, using <i>Klhl12</i> intestinal knockout mice, we demonstrate that KLHL12 is not required for chylomicron secretion and lipid absorption. These findings suggest that the regulation of ApoB-containing lipoprotein secretion differs between the liver and the intestine.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E233-E240"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537770","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":"Sugar type and route of delivery influence insulin and glucose-dependent insulinotropic polypeptide responses in rats.","authors":"A Valentina Nisi, Myrtha M L Arnold, Ginger D Blonde, Lindsey A Schier, Graciela Sanchez-Watts, Alan G Watts, Wolfgang Langhans, Alan C Spector","doi":"10.1152/ajpendo.00460.2024","DOIUrl":"10.1152/ajpendo.00460.2024","url":null,"abstract":"<p><p>To help resolve the characteristics of orally stimulated endocrine responses to sugar, we developed a novel rat preparation with surgically implanted intraoral (IO) and intragastric (IG) cannulas for stimulus delivery, along with jugular vein catheters for blood sampling, and tested the effects of 1-min and 10-min IO versus IG infusions (1 mL/min) of 1.0 M glucose on plasma levels of insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucose. Oral glucose delivery (1 min and 10 mins) caused a greater (<i>P</i> ≤ 0.05) early rise (1 min) in insulin levels than gastric glucose delivery, also reflected in the 3-min area under the curve (AUC). The 10-min, but not the 1-min, IO glucose infusion also caused a greater (<i>P</i> ≤ 0.05) increase in GIP levels than the IG infusions, as evidenced by the 3-min AUC. Oral delivery of 1.0 M fructose produced marginally (but significantly) higher insulin and GIP levels than gastric fructose delivery, although the difference appeared much smaller than that observed for isomolar glucose, suggesting some degree of chemospecificity and the involvement of a taste type 1 receptor-independent mechanism. Our triple cannulation/catheterization rat preparation is well suited to assess endocrine responses to oral stimulation. By comparing the effects of stimulus infusion into the oral cavity (oral + postoral stimulation) with the stimulus infusion directly into the stomach (only postoral stimulation), we confirmed the primacy of glucose to orally trigger an increase in circulating insulin while controlling for changes in plasma glucose. This approach offers promise for reliably characterizing orally stimulated endocrine responses in rats and potentially in other animal models as well.<b>NEW & NOTEWORTHY</b> We describe an innovative preparation that can effectively characterize orally stimulated endocrine responses during ongoing ingestion in rats. We found that glucose orally triggered an early rise in not only plasma insulin-which in some circumstances was present even as glycemia increased-but also glucose-dependent insulinotropic polypeptide, albeit more weakly. These endocrine responses to orally delivered fructose were weak or nonexistent, confirming the primacy of glucose as the key monosaccharide stimulus.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E210-E225"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493414","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":"Quantitative estimation of disposition index from postprandial glucose data across the spectrum of glucose tolerance.","authors":"Michele Schiavon, Adrian Vella, Chiara Dalla Man","doi":"10.1152/ajpendo.00407.2024","DOIUrl":"10.1152/ajpendo.00407.2024","url":null,"abstract":"<p><p>Disposition index (DI), defined as the product of insulin sensitivity and β-cell responsivity, is the best measure of β-cell function. This is usually assessed from plasma glucose and insulin, and sometimes C-peptide, data either from surrogate indices or model-based methods. However, the recent advent of continuous glucose monitoring (CGM) systems in non-insulin-treated individuals raises the possibility of its quantification in outpatients. As a first step, we propose a method to assess DI from glucose concentration data only and validated it against the oral minimal model (OMM). To do so, we used data from two clinical dataset with mixed meal tolerance test (MTT) studies in non-insulin-treated individuals: the first consisted of 14 individuals with type 2 diabetes studied twice, either after receiving a DPP-4 inhibitor or a placebo before the meal, whereas the second consisted of 62 individuals with and without pre- or type 2 diabetes. A third, simulated, dataset consisted of 100 virtual subjects from the Padova Type 2 Diabetes Simulator was used for additional tests. Plasma glucose, insulin, and C-peptide concentrations were used to estimate the reference DI from the OMM (DI^MM), whereas glucose data only were used to calculate the proposed DI (DI^G). DI^G was well correlated with DI^MM in both the clinical and simulated datasets (<i>R</i> between 0.88 and 0.79, <i>P</i> < 0.001), and exhibited the same between-visit or between-group pattern. DI^G can be used to assess therapy effectiveness and degree of glucose tolerance using glucose data only, paving the way to potentially assess β-cell function in real-life conditions using CGM.<b>NEW & NOTEWORTHY</b> The advent of continuous glucose monitoring (CGM) in non-insulin-treated individuals raises the possibility of quantifying disposition index (DI), a key metric of β-cell function usually assessed in research settings, in outpatients. A method for DI estimation from postprandial glucose data only (DI^G) was developed and validated against a reference. DI^G can be used to assess therapy effectiveness and degree of glucose tolerance in non-insulin-treated individuals, paving the way for its quantification in real-life conditions from CGM devices.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E354-E366"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615833","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":"Counterregulatory responses of healthy cats to insulin-induced hypoglycemia.","authors":"Jocelyn Mott, Christopher Adin, Chiquitha Crews, Marc Salute, Antonio Maria Tardo, Lauren Porter, Alisa Berg, Chen Gilor","doi":"10.1152/ajpendo.00269.2024","DOIUrl":"10.1152/ajpendo.00269.2024","url":null,"abstract":"<p><p>In health, insulin-induced hypoglycemia (IIH) activates counterregulatory hormone responses and parasympathetic (PS) and sympathoadrenal systems, which leads to increased glucagon secretion. In diabetes mellitus, these responses are impaired, resulting in greater severity and delayed recovery from hypoglycemia. These counterregulatory responses in health and disease have been documented in humans, rodents, and dogs, but not yet in cats. The aim of this study was to describe and quantify glucagon, PS, and cortisol responses in healthy purpose-bred cats at increasing levels of IIH. Glucagon, cortisol, and pancreatic polypeptide (PP) were measured at euglycemia and during stepped hyperinsulinemic-hypoglycemic clamps at two levels of glycemia: moderate hypoglycemia [blood glucose (BG) ∼60 mg/dL] and severe hypoglycemia (BG ∼45 mg/dL). At moderate hypoglycemia, a cortisol response occurred with no change in PP and glucagon from baseline. With severe hypoglycemia, both glucagon and PP concentrations decreased from baseline and were not supportive of glucagon and parasympathetic activation in response to IIH. Although cortisol increases during IIH, the counterregulatory response to IIH in healthy cats differs from other species, in that glucagon and PS responses were not detected. Moreover, in face of constant inhibition by IIH, glucagon secretion seems dependent on glucose, decreasing when glucose infusion rates were decreased. Understanding counterregulatory responses to hypoglycemia in healthy cats is the first step to exploring how diabetes might impair these responses in cats, as seen in other species.<b>NEW & NOTEWORTHY</b> Counterregulatory responses to insulin-induced hypoglycemia (IIH) in cats may be unique and species specific. Glucagon concentrations decrease in cats in response to IIH. In face of constant rate hyperinsulinemia, a decrease in glucose infusion is associated with a further decrease in glucagon concentrations. A similar pattern occurred with pancreatic polypeptide responses. Cats respond to hypoglycemia by increasing cortisol. These findings may have implications for the treatment of hypoglycemia in insulin-treated diabetic cats.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E276-E289"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514394","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":"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":3.1,"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":"Metabolic pathways and male fertility: exploring the role of Sertoli cells in energy homeostasis and spermatogenesis.","authors":"Zi-Feng Chen, Yi-Feng Shen, Da-Wei Gao, Deng-Feng Lin, Wen-Zhe Ma, De-Gui Chang","doi":"10.1152/ajpendo.00074.2025","DOIUrl":"10.1152/ajpendo.00074.2025","url":null,"abstract":"<p><p>Globalization has driven a surge in noncommunicable diseases, including metabolic disorders, which are major global health challenges. These disorders, fueled by high-calorie diets, sedentary lifestyles, and gut microbiota imbalances, disrupt energy metabolism, gastrointestinal function, and vitamin and trace element homeostasis. Sertoli cells provide the metabolic and structural support essential for germ cell development within the seminiferous epithelium. This review examines how metabolic disorders affect male reproductive health, focusing on glucose, lipid, and vitamin metabolism, as well as the gut-testis axis, in relation to Sertoli cell function and the blood-testis barrier (BTB) integrity. Glucose metabolism in Sertoli cells provides lactate to germ cells, which is crucial for spermatogenesis. However, metabolic stressors, such as diabetes, impair glucose transport and lactate production, compromising energy supply. Lipid metabolism, including fatty acid oxidation and lipid droplet dynamics, is essential for energy homeostasis in Sertoli cells. Moreover, the gut microbiota further influences Sertoli cells and BTB integrity via metabolites, such as short-chain fatty acids, which enhance barrier function and reduce inflammation. Conversely, dysbiosis and microbially derived lipopolysaccharides induce oxidative stress and immune responses, leading to BTB disruption and infertility. Deficiencies or imbalances in the levels of these vitamins and trace elements can impair spermatogenesis. This review highlights the complex interplay between metabolic pathways and Sertoli cell function, their collective impact on male fertility, and provides a basis for developing targeted therapeutic strategies, including metabolic modulators, vitamin supplementation, and gut microbiota interventions, to mitigate the effects of metabolic disorders on spermatogenesis and fertility.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E160-E178"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309362","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}