American journal of physiology. Endocrinology and metabolism最新文献

Glucagon resistance impairs amino acid metabolism in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanism remains unclear. Given that glucagon mediates its effects through cyclic adenosine monophosphate (cAMP), impaired cAMP responses have been proposed as the molecular center of glucagon resistance. In this study, we investigated if the glucagon-induced cAMP response is impaired by metabolic dysfunction, thereby contributing to glucagon resistance. Plasma cAMP responses to an intravenous bolus injection of glucagon were analyzed in 64 individuals with or without MASLD and type 1 diabetes. In parallel, hepatic cAMP secretion during glucagon stimulation was determined using in situ liver perfusion in lean and diet-induced obese (DIO) mice with hepatic steatosis. Participants with obesity and MASLD showed higher baseline plasma cAMP, but neither glucagon, insulin, steatosis, nor BMI could explain this. Across all groups, glucagon-induced cAMP responses were similar. Similarly, DIO mice displayed preserved hepatic cAMP release in response to glucagon compared with lean controls. These findings suggest that the glucagon-induced cAMP response is maintained in MASLD independently of insulin. Thus, hepatic glucagon resistance in MASLD may be due to non-cAMP-dependent signaling.NEW & NOTEWORTHY Here, we investigate the molecular cause for hepatic glucagon resistance in MASLD. We demonstrate that cAMP responses to glucagon are preserved in both humans and mice with liver steatosis, suggesting that the defect lies downstream of cAMP production. These findings redefine the understanding of glucagon resistance and point toward alternative mechanisms beyond second messenger activation.

The metabolic endotoxemia hypothesis proposes that low levels of gut-derived lipopolysaccharides (LPS) act in a hormone-like manner to influence metabolism, contributing to obesity and dysregulation of glucose homeostasis. However, due to methodological limitations, it remains unclear whether a significant amount of bioactive gut-derived LPS reaches the bloodstream and, if so, whether it has a meaningful impact on metabolic processes. In addition, there are several theoretical challenges regarding the coherence of the metabolic endotoxemia hypothesis, raising questions about its validity. Here, in the light of recent literature, we critically review arguments for and against the metabolic endotoxemia hypothesis.

Individuals with obesity and endurance exercise-trained athletes both exhibit excess lipid content in their skeletal muscle compared with healthy, sedentary individuals, yet they experience vastly different health outcomes. Lipids taken up from the circulation contribute to lipid stored in muscle in both populations. Differences in the muscle uptake of plasma non-esterified fatty acids (NEFA) and fatty acids derived from plasma triacylglycerol (TG) between individuals with obesity and endurance-trained athletes have not been systematically examined. In athletes, muscle actively regulates the uptake of TG-derived fatty acids through upregulation of the activity of muscle lipoprotein lipase-the enzyme responsible for the intravascular hydrolysis of TG, a phenomenon evident in the fasting state. In contrast, in individuals with obesity, skeletal muscle functions as a passive recipient of TG-derived fatty acids, an event that becomes quantitively more important when the plasma TG concentrations increase during the postprandial state. Considerable differences in the muscle uptake of plasma NEFA between athletes and individuals with obesity are less evident. These observations indicate mechanistic differences in the regulation of plasma TG-derived fatty acids uptake in muscle between individuals with obesity and endurance-trained athletes in shaping the excess lipid content in their muscles. Moreover, this evidence highlights the need for targeting a reduction in plasma TG in the postprandial state when aiming to attenuate lipid accumulation in muscle in the pathophysiology of obesity.

Cellular communication network factor 5 (CCN5; WISP2) is a matricellular protein. Our previous studies suggest that CCN5 promotes the proliferation and survival of pancreatic β-cells, thereby conferring metabolic advantages. A recent report indicated that a systemic deficiency in CCN5 expression leads to increased adiposity, glycemia, and insulin resistance. These conditions worsen when subjected to a high-fat diet (HFD). To further understand the metabolic roles of endogenous CCN5, we reassessed CCN5 knockout mice that were fed either a chow diet or a 60% HFD. In contrast to the previous report, our findings reveal that CCN5 knockout mice of both sexes maintain normal lean/fat mass, body weight, glycemia, insulin levels, and insulin sensitivity when fed a chow diet. However, the expression of the CCN5 gene seems to be essential for maintaining normal β-cell growth. Even under the stress of extended HFD feeding, CCN5 knockout mice exhibited similar weight gain and did not show an elevation in glycemia. Male knockout mice displayed improved glucose tolerance, insulin sensitivity, and a slight decrease in glycemia compared with wild-type counterparts. Interestingly, the lack of CCN5 did not affect obesity-induced β-cell compensation. These findings further reinforce the role of CCN5 as a comprehensive metabolic regulator, although the effects could be sex specific. In male mice affected by diet-induced obesity, the endogenous expression of CCN5 seems to have a negative impact on insulin and glucose tolerance. Under different physiological conditions, the systemic effects of CCN5 and its specific influence on β-cells may interact to shape the metabolic outcomes.NEW & NOTEWORTHY This study challenges prior findings by demonstrating that CCN5 knockout mice maintain normal body weight and glucose tolerance on a chow diet but exhibit impaired β-cell expansion. Strikingly, under a high-fat diet, male knockout mice display enhanced glucose tolerance without compromising β-cell compensation. These results suggest that CCN5's influence on metabolism is context-dependent, shaped by both diet and sex, and may critically modulate metabolic outcomes through its regulatory effects on β-cells.

The incidence of type 1 diabetes (T1D) has increased in recent years. Although extensive research has focused on immune damage to insulin-producing beta cells, the pathophysiological effects on other endocrine cells within pancreatic islets remain less well-documented. This study investigates the changes in the number and proportion of alpha, beta, and delta cells, as well as hormone secretion, during the progression of autoimmunity in nondiabetic nonobese diabetic (NOD) mice at different ages. Our findings reveal significant heterogeneity in islet size, endocrine cell composition, and degree of immune infiltration. We propose a novel classification system for islet subtypes based on this observed heterogeneity. Notably, we noticed an age-related increase in delta cells in older nondiabetic NOD mice. In addition, we observed an increase in glucagon and somatostatin double-positive cells following immune cell infiltration in nondiabetic mice. Our further analysis demonstrated that these double-positive cells represent a transdifferentiation process from alpha cells to delta cells, mediated by an alpha cell dedifferentiation intermediate. Moreover, our results indicated that the increased presence of delta cells and somatostatin in pancreatic islets significantly inhibits alpha cell function during the progression of autoimmunity. Thus, our findings provide valuable insights into the dynamic changes in alpha and delta cells throughout the natural history of T1D.NEW & NOTEWORTHY The NOD mouse is widely used as an T1D animal model. Although the mice have the same genetic background, approximately 20% of female NOD mice do not develop diabetes. In this study, we reveal that alpha cells dedifferentiate and then transdifferentiate into delta cells during the progression of autoimmunity in nondiabetic NOD mice. The increased delta cells secrete more somatostatin, which inhibits alpha cell secretion of glucagon, thereby potentially attenuating the increase in blood glucose levels in these mice.

Metabolic diseases such as diabetes, hypertension, and fatty liver, driven by obesity, are increasing due to overnutrition and physical inactivity. In these conditions, the ribosomal stress response (RSR) represents a previously underexplored mechanism. Dysregulated production of reactive oxygen species (ROS) from sources including NADPH oxidase and the mitochondrial electron transport chain leads to oxidative stress, which can induce ribosome collisions. This, in turn, activates ZAKα and the RSR pathway, driving metabolic dysfunction through stress-activated kinases such as c-Jun N-terminal kinase and p38. Elucidating the interplay between reactive oxygen species, ribosomal stress, and metabolic disease could open new therapeutic avenues. Dietary interventions, including polyunsaturated fatty acids and natural antioxidants, have the potential to reduce oxidative stress and improve metabolic health. The aim of this review is to highlight the link between ROS and ribosomal stress, with a focus on targeting ribosome collisions as a therapeutic strategy in metabolic disorders. Future studies should also establish reliable biomarkers of aberrant oxidative stress to guide clinical interventions for metabolic disease.

High-intensity interval training (HIIT) may improve metabolic outcomes in people with type 2 diabetes (T2D) and prediabetes (PD). This randomized controlled trial assessed plasma lipidomic differences between overweight participants [body mass index (BMI) > 25 kg/m²] with normal glucose tolerance (NGT) (n = 74), PD (n = 60) or newly-diagnosed T2D (n = 26), and the effects of a combined HIIT and progressive resistance training (PRT) intervention on circulating lipids. Participants were randomized to either a stretching or HIIT + PRT protocol. Fasted plasma was collected at baseline and after 12 wk. Plasma lipids, d- and l-serine, and d- and l-alanine were quantified with liquid chromatography-tandem mass spectrometry. Plasma lipidomics revealed significantly lower levels of sphingomyelin and lysophosphatidylcholine (LPC) and higher diacylglycerol and deoxyceramide species in T2D compared with NGT or PD. The HIIT + PRT intervention significantly reduced circulating deoxyceramides in the T2D group. We investigated the basis for elevated atypical deoxyceramides in T2D, which use l-alanine rather than l-serine as biosynthetic substrates. Serine levels were unchanged; however, l-alanine and d-alanine were increased in T2D. Total diacylglycerol, l-alanine, and d-alanine positively correlated with fasting glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glycated hemoglobin, and liver fat, whereas sphingomyelin and LPC inversely correlated with fasting glucose and HOMA-IR. The l-alanine:l-serine ratio positively correlated with deoxyceramide levels, but was unaltered by the HIIT + PRT intervention. This study reveals plasma lipidomic perturbations in T2D, establishing that excess l-alanine may underpin elevated metabolically-adverse deoxyceramide levels in T2D, and demonstrates that a 12-wk HIIT + PRT protocol significantly reduces deoxyceramides in individuals with T2D independently of the plasma l-alanine:l-serine ratio.NEW & NOTEWORTHY We have found that the baseline plasma lipidome differs substantially between people who are overweight with normal glucose tolerance or prediabetes, compared with type 2 diabetes, and that the 12-wk exercise protocol instituted reduces levels of metabolically adverse potentially toxic deoxyceramide species in type 2 diabetes. Moreover, excess plasma l-alanine levels may account for the baseline elevated deoxyceramides. This study thus identifies that low-volume exercise can improve novel aspects of the lipidome in metabolic health.

Vasopressin plays a central endocrine role in water homeostasis by activating the arginine vasopressin receptor 2 (AVPR2) receptor in renal collecting duct cells. Mutations in AVPR2 are a leading cause of X-linked nephrogenic diabetes insipidus (NDI), a disorder marked by renal insensitivity to vasopressin, leading to polyuria, polydipsia, and hypernatremia. We identified a novel truncating AVPR2 mutation (c.570dup; D191*) in a pediatric patient with NDI and investigated its molecular and functional consequences using a renal epithelial cell model. The D191* mutant exhibited marked reduction in total and surface receptor expression due to intracellular retention and rapid proteasomal degradation. Functional assays revealed that 1-deamino-8-d-arginine vasopressin (dDAVP) stimulation failed to elicit cAMP production or activate downstream signaling targets, including CREB and ERK1/2, in cells expressing the mutant receptor. Aquaporin-2 (AQP2) membrane translocation, essential for water reabsorption, was also impaired. Notably, treatment with forskolin or 8-bromo-cAMP restored cAMP levels, reactivated downstream signaling, and rescued AQP2 localization to the apical membrane, independent of AVPR2 activation. These findings uncover the pathophysiological mechanism by which D191* impairs vasopressin signaling and suggest that bypassing the receptor via direct cAMP pathway activation offers a promising therapeutic strategy for NDI. This study highlights the endocrine relevance of precision molecular diagnostics and supports functional rescue approaches for receptor-based disorders.NEW & NOTEWORTHY This study identifies and functionally characterizes a previously unreported truncating AVPR2 mutation (c.570dup; p.D191*) causing congenital nephrogenic diabetes insipidus. Using renal epithelial cell models, the authors show that D191* leads to receptor misfolding, proteasomal degradation, absent cAMP signaling, and failure of aquaporin-2 trafficking. Remarkably, forskolin and 8-bromo-cAMP bypass the defective receptor to restore downstream signaling and water channel localization, highlighting a potential therapeutic strategy of receptor-independent cAMP activation for AVPR2-null nephrogenic diabetes insipidus.

Acute angiotensin II (Ang II) type 1 receptor (AT₁R) blockade recruits skeletal and cardiac muscle microvasculature in healthy humans without altering insulin-mediated whole body glucose disposal. We aimed to elucidate the vascular and metabolic effects of Ang II type 2 receptor (AT₂R) stimulation in healthy humans. Following AT₁R blockade with candesartan, healthy adults received an intravenous infusion of either Ang II or saline for 180 min with or without a euglycemic hyperinsulinemic clamp superimposed during the final 120 min. Skeletal and cardiac muscle microvascular perfusion, brachial artery diameter and flow velocity, augmentation index, pulse wave velocity (PWV), and insulin-mediated whole body glucose disposal were assessed. In the presence of AT₁R blockade, Ang II infusion did not alter hemodynamic parameters or insulin-mediated whole body glucose disposal. Both insulin and Ang II increased skeletal and cardiac muscle microvascular perfusion; however, superimposing insulin on Ang II infusion did not further augment microvascular perfusion in either tissue. Infusion of Ang II, insulin, or their combination significantly increased total brachial artery blood flow. Ang II infusion increased PWV, an effect attenuated by insulin. Selective stimulation of AT₂R significantly enhanced skeletal and cardiac muscle microvascular perfusion and total tissue blood flow without altering insulin's vascular and metabolic actions in healthy humans. These findings may help explain the cardiovascular and metabolic benefits observed in individuals treated with AT₁R blockers.NEW & NOTEWORTHY The renin-angiotensin system critically regulates tissue perfusion, insulin action, and metabolism. Angiotensin II, via its type 1 receptor (AT₁R), promotes vasoconstriction and insulin resistance. In this study, we systemically infused angiotensin II in healthy humans during AT₁R blockade to selectively activate the type 2 receptor (AT₂R). Angiotensin II significantly increased skeletal and cardiac muscle microvascular perfusion and total blood flow without affecting insulin's vascular or metabolic actions, offering mechanistic insights into AT₁R blockers' cardiometabolic benefits.

Sepsis is a condition marked by physiologic dysregulation secondary to infection and is influenced by the nutritional state. Despite several preclinical studies and clinical trials examining nutrition and supplements in sepsis, there are no clear guidelines. Omega-3 fatty acids are polyunsaturated fatty acids with anti-inflammatory properties, represented mainly by alpha-linolenic (ALA, C18:3), eicosapentaenoic (EPA, C20:5), and docosahexaenoic (DHA, C22:6). Since sepsis is characterized with high levels of inflammation and subsequent organ dysfunction, we hypothesized that omega-3 ingestion would improve sepsis survival by attenuating inflammation via activation of GPR120 in immune cells. Here, we aimed to experimentally explore the role of omega-3 and the receptor that mediates their anti-inflammatory functions, GPR120, during sepsis. To evaluate GPR120 functionality, acute inflammation was induced via lipopolysaccharide (LPS) treatment in Raw 264.7 cells, 3T3-L1 cells, bone marrow-derived macrophages, and primary adipocytes. To evaluate the impact of omega-3 in sepsis, C57BL/6J mice were supplemented with omega-3 before LPS administration or cecal ligation and puncture (CLP) surgery. GPR120 mRNA expression decreased during inflammation. Unexpectedly, omega-3 supplementation preceding CLP worsened sepsis survival in mice. In addition, omega-3 did not affect inflammatory markers such as TNFα, IL1β, IL10, and IL6. Overall, our findings that omega-3 do not influence inflammation or improve survival in sepsis are surprising, given that omega-3 supplementation is recommended for the prevention of cardiovascular diseases due to its anti-inflammatory properties. The negative impact of omega-3 supplementation on survival in the CLP model raises caution for future clinical studies involving sepsis.NEW & NOTEWORTHY This study uncovers worsening in survival in mice models pretreated with omega-3 supplementation. We demonstrated decreased Ffar4 receptor expression in macrophages and adipocytes when challenged with acute and chronic sepsis models in vitro and in vivo. This study offers insight into the role of omega-3 supplementation in the context of sepsis, highlighting concerns and underscoring the need for further investigation.