American journal of physiology. Endocrinology and metabolism最新文献

Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, poses an increasing global health burden among aging populations. Despite decades of research, its pathogenesis remains incompletely understood, and effective therapies are urgently needed. Growing evidence links AD progression to inflammation and type 2 diabetes mellitus (T2DM), with hyperglycemia, insulin resistance, and chronic inflammation synergistically driving neuronal dysfunction. These factors perpetuate a pathogenic "metabolic-inflammatory cycle": inflammatory cytokines disrupt insulin signaling, exacerbating insulin resistance, which further amplifies neuroinflammation. Whereas anti-inflammatory and antidiabetic drugs show limited clinical efficacy in AD, bitter compounds, natural and synthetic agents with pleiotropic bioactivities, offer a novel therapeutic avenue. Notably, bitter compounds such as the alkaloid berberine, the flavonoid naringenin, and synthetic bitter compounds such as denatonium benzoate and metformin exhibit dual anti-inflammatory and metabolic regulatory effects. Preclinical studies have demonstrated their ability to suppress neuroinflammation, restore insulin sensitivity, and mitigate amyloid/tau pathology, potentially disrupting the metabolic-inflammatory cycle. Emerging insights also highlight their modulation of the gut-brain axis, linking intestinal homeostasis to neuroprotection. This mini-review synthesizes current evidence on the interplay of T2DM and inflammation in AD, emphasizing how bitter compounds target immunometabolic cross talk. This review also briefly discusses the metabolic and anti-inflammatory properties of bitter compounds via the gut-brain axis, alongside their potential for combination with current anti-AD drugs, suggesting multidisciplinary collaboration. Further mechanistic studies and clinical validation are warranted to translate bitter compound-based therapies into practice, addressing unmet needs in AD management.

Aging is associated with alterations in immune cell function, contributing to age-related diseases and frailty. As peripheral blood mononuclear cells (PBMCs) are key drivers of the immune response, we investigated their transcriptome using RNA-sequencing before and immediately after a single bout of high-intensity knee-extension exercise in young (young; n = 7, 23 ± 4 yr) and older individuals (old; n = 8, 65 ± 7 yr). We used bioinformatics analyses to identify the biological processes and pathways that may be altered with age and in response to acute exercise. At baseline, 665 genes differed between young and old, with notable differences in pathways involved in DNA damage/telomere stress-induced senescence, NAD signaling pathway, and oxidative stress-induced senescence. After the exercise bout, 53 genes were differentially expressed in young, whereas 1,026 genes changed in old. In young, the enriched processes and predicted pathways were linked to natural killer cells, whereas in old, these pathways were associated with cell signaling immune responses. Finally, 26 genes exhibited similar responses to exercise between groups, enriching the biological process of natural killer cell-mediated immunity regulation. Our findings indicate that PBMC gene expression and the response to acute exercise are altered with aging, where exercise induces more pronounced PBMC transcriptomic adaptations in the old. In addition, although aging is associated with increased expression of genes linked to cellular dysfunction and suppressed immune function, acute exercise attenuated these age-related differences by downregulating the genes related to those pathways. Finally, acute exercise activated similar immune-related pathways in both age groups.NEW & NOTEWORTHY This study demonstrates that aging alters the transcriptional landscape of PBMCs at rest and in response to acute high-intensity exercise. Older adults exhibited greater transcriptomic responsiveness to exercise, particularly in pathways related to immune signaling and cellular stress. Notably, exercise elicited shared activation of NK cell-mediated processes across age groups, suggesting a conserved immunomodulatory effect. These findings provide molecular insight into how aging and exercise interact to shape immune cell function.

Although high-density lipoprotein (HDL) has cardiometabolic protecting properties, interventions to raise HDL cholesterol concentration have failed to improve cardiometabolic health. Hence, HDL composition and functionality might be key factors in its anti-atherogenic capacity. Alterations in HDL composition have been linked to pathophysiological states, whereas endurance training is known to increase HDL concentration with a shift toward bigger particle sizes, but its effect on the HDL composition is not well understood. Therefore, we selected subjects with the highest and the lowest aerobic fitness from a study group resembling population and compared HDL protein and lipid composition and serum metabolic profiles using mass spectrometry, thin-layer chromatography, and nuclear magnetic resonance spectroscopy methodologies. High aerobic fitness and normal body composition were associated with elevated proportion of cholesteryl esters suggesting improved cholesterol metabolism. Low aerobic fitness and elevated amount of adipose tissue increased the proportion of phospholipids in HDL, whereas elevated proportion of triacylglycerols was associated only with higher adiposity level, suggesting modulations in particle surface fluidity and tendency for particle catabolism. Serum metabolic profiles supported the observations highlighting differences in the concentration of large HDL₂ particles, very-low-density lipoprotein, and serum triacylglycerols between the groups. Higher adipose tissue level increased proteins related to inflammation and hemostasis in HDL, whereas normal body composition was linked to increased amounts of apolipoprotein A-II and C-II suggesting improved HDL composition. Results suggest that high aerobic fitness and normal body composition have positive effects on HDL composition through reduced inflammation and better serum lipid homeostasis.NEW & NOTEWORTHY High aerobic fitness is linked to elevated HDL concentration and a shift toward bigger particle sizes, but its effect on the HDL composition is not well understood. For the first time, this study compared HDL lipid and proteomic compositions between two groups with differences in aerobic fitness level and body composition. The findings suggest positive modulations in HDL composition due to regular physical activity associated with better body composition, inflammation status, and serum lipid homeostasis.

The prediction and treatment of spontaneous preterm labor (sPTL) are critical challenges due to obscure etiology and lack of highly specific and sensitive testing methods. Here, we extended the application of noninvasive prenatal testing into the field of sPTL prediction using high-throughput small RNA sequencing to screen the potential biomarkers for sPTL in maternal peripheral blood. We found that hsa-miR-150-5p and hsa-miR-512-3p decreased in the patients affected by sPTL, compared with either term labor or term not labor patients. The change of hsa-miR-150-5p is validated using quantitative PCR with the area under the receiver operating characteristic curve (AUROC) of hsa-miR-150-5p around 0.8272. In the discovery set, hsa-miR-150-5p exhibited an AUROC of approximately 0.8508, which was validated in an independent cohort, accurately classifying preterm samples with an AUROC of 0.8010. Moreover, we showed miR-150-5p inhibited migration and invasion of chorionic cells by directly targeting a disintegrin and metalloproteinase 19 (ADAM19). The significant increase of ADAM19 in chorion from patients affected by sPTL further indicates its inverse correlationship with miR-150-5p. ADAM19 functions as a sheddase of membrane-bound TNF-α to release the TNF-α trimer into the extracellular environment, reciprocally inducing the expression of ADAM19 to form a regenerative cycle and augmenting the migration and invasion of fetal membrane cells. Remarkably, the predictive efficiency of miR-150-5p for premature rupture of membranes (PROMs)-related sPTL sharply rose to 94.21%, indicating its potential as a biomarker for preterm premature rupture of membranes (pPROMs). These findings establish miR-150-5p both as a promising noninvasive biomarker for identifying the risk of sPTL and a key regulator in pathogenesis of pPROM.NEW & NOTEWORTHY MiR-150-5p is identified as a potential noninvasive biomarker associated with sPTL and regulates chorionic cell migration, invasion, and adhesion by targeting ADAM19, a member of the ADAM family, contributing to premature rupture of fetal membranes. These findings provide new insights into the molecular mechanisms of sPTL and suggest that targeting the miR-150-5p/ADAM19 axis may offer novel therapeutic strategies.

Accurately assessing whole body heat production requires reliable thermometry methods. In mice, common approaches include rectal temperature (RT) measurement, infrared (IR) thermography, and implanted probes. However, factors such as stress, handling, surgery, and variability limit their applicability for evaluating thermogenesis. The Thermal Gradient Ring (TGR), widely used in neuropathic pain and ion channel studies, consists of a circular structure with 12 temperature zones and an integrated camera for real-time behavior monitoring. This system allows for precise analysis of independent behavioral measures, including preferred temperature (PT), distance accumulation in the zones, locomotion pattern, and zone occupancy over time, thereby offering an indirect readout of thermoregulatory state. In this study, we evaluated TGR as a noninvasive tool to detect thermoregulatory behavior adaptations, quantifying zone occupancy time, mobility patterns across temperature gradients, and preferred temperature. Using models with both elevated (β-adrenergic stimulation and high-fat diet feeding) and reduced core body temperature [brown adipose tissue (BAT) lipectomy, uncoupling protein 1 (UCP1) deficiency, and cold exposure], we found that the TGR system reliably detects context-specific thermoregulatory behaviors that contribute to energy homeostasis, while simultaneously serving as a quantitative tool for evaluating thermogenic status. These findings suggest that TGR is a valuable tool for metabolic research, offering a reliable additional assessment for thermogenesis in mice.NEW & NOTEWORTHY The integration between adaptive thermogenesis and behavioral strategies governing metabolic state regulation in mice remains poorly characterized. Using a TGR system, we developed and validated a novel methodology for noninvasive, unbiased, and continuous monitoring of behavior-driven thermogenic capacity. Using loss- and gain-of-function models of BAT thermogenesis, we identified distinct behavioral strategies, mice dynamically adjusted locomotor activity and thermal zone occupancy to modulate heat production, directly reflecting their real-time monitoring of metabolic status.

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 (n = 6) and low (n = 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 (P < 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 (r = 0.57, P < 0.05), but not in the controls. Fat oxidation averaged over 60-120 min was significantly greater with menthol in the high BAT group (P < 0.05) compared with the low BAT group. Rectal temperature at 120 min was significantly higher with menthol treatment in the high BAT groups (P < 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.NEW & NOTEWORTHY 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.

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.NEW & NOTEWORTHY 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.

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 Klhl12 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, Klhl12 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 Klhl12 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.NEW & NOTEWORTHY 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 Klhl12 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.

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 (P ≤ 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 (P ≤ 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.NEW & NOTEWORTHY 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.

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 (R between 0.88 and 0.79, P < 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.NEW & NOTEWORTHY 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.