American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Regulation of perinatal estrogen levels on primordial follicle formation and activation in mouse.","authors":"Rui Xu, Lu Yin, Yiqian Zhang, Yinxiang Niu, Sihai Lu, Yaju Tang, Sha Peng, Menghao Pan, Baohua Ma","doi":"10.1152/ajpendo.00026.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00026.2025","url":null,"abstract":"<p><p>Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the levels of estrogen are fluctuating. Whether estrogen plays a role in primordial follicle formation and activation, and its mechanism are still not fully elucidated. In this study, estrogen remained at high levels before birth and declined after birth. When fetal mouse ovaries (E16.5) were cultured in vitro, higher levels (10 nM) of estrogen maintained the germ cell cysts, prevented primordial follicles from forming prematurely, and promoted the full differentiation of oocytes. Furthermore, it was found that estrogen-regulated JNK-signal pathway through both nuclear and membrane receptors, thereby inhibited the degradation of E-cadherin and maintained the germ cell cysts. After birth, ovarian estrogen concentration decreases and is accompanied by the activation of primordial follicles. Hence, the ovaries of newborn mice (P3) were treated with lower concentrations (0.1 nM) of estrogen to investigate the effect of estrogen on primordial follicle activation. The results demonstrated that estrogen regulated the protein expression of cAMP synthase adenylyl cyclase 3 (ADCY3) through the membrane receptor G-protein-coupled estrogen receptor (GPER), increased the level of cAMP in the ovary, and activated the cAMP-PKA signaling pathway to promote the activation of primordial follicles. This study revealed the regulatory role of perinatal estrogen levels on primordial follicle formation and activation before and after birth, which would help to better understand the potential physiological effect of estrogen in vivo.<b>NEW & NOTEWORTHY</b> In this study, the roles and underlying mechanisms of perinatal estrogen level changes in primordial follicle formation and activation in mice were elucidated. The elevated estrogen levels before birth inhibited the premature formation of primordial follicles and enhanced the quality of oocyte differentiation. Conversely, the reduced estrogen levels following birth promoted the activation of primordial follicles.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E772-E786"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956570","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":"Catabolic to anabolic transition during nutritional rehabilitation of female adolescents with anorexia nervosa.","authors":"Yael Levy-Shraga, Idit Ron, Adi Enoch-Levy, Rina Hemi, Hannah Kanety, Ido Wolf, Daniel Stein, Amir Tirosh, Tami Rubinek, Dalit Modan-Moses","doi":"10.1152/ajpendo.00523.2024","DOIUrl":"10.1152/ajpendo.00523.2024","url":null,"abstract":"<p><p>Anorexia nervosa (AN) is associated with profound changes in glucose homeostasis, activity of the GH-IGF-1 axis, and adipose tissue, bone, and protein metabolism. We aimed to characterize the transition from a catabolic to anabolic state during the nutritional rehabilitation of female adolescent inpatients with AN. The study comprised 41 patients (aged 15.6 ± 1.6 yr). Blood samples were obtained at the time of admission and upon attainment of target weight. A subgroup of 18 patients also had blood samples obtained during the early refeeding period. Changes in body mass index (BMI) and BMI-SDS during hospitalization (5.1 ± 2.0 mo) were positively correlated with changes in markers of anabolism including IGF-1 (<i>r</i> = 0.424, <i>P</i> = 0.006), procollagen type I N-terminal propeptide (P1NP) (<i>r</i> = 0.375, <i>P</i> = 0.016), klotho (<i>r</i> = 0.468, <i>P</i> = 0.002), and alkaline phosphatase (ALP) (<i>r</i> = 0.051, <i>P</i> = 0.001) and were negatively correlated with the change in cortisol levels (<i>r</i> = -0.331, <i>P</i> = 0.035). Furthermore, changes in markers of anabolism were intercorrelated. IGF-1 increased consistently throughout the study period (<i>P</i> < 0.001); however, other variables showed a biphasic pattern. During the early refeeding period, there was a decrease in C-terminal telopeptides of type I collagen (CTX-1) (<i>P</i> < 0.001), uric acid (<i>P</i> < 0.001), cortisol (<i>P</i> = 0.056), fatty acid-binding protein 4 (FABP4) (<i>P</i> = 0.04), and klotho (<i>P</i> = 0.038) levels, whereas urea/creatinine ratio (UCR) (<i>P</i> = 0.045) increased. During the later phase, there was an increase in ALP (<i>P</i> = 0.039), insulin (<i>P</i> = 0.04), homeostatic model assessment for insulin resistance (HOMA-IR) (<i>P</i> = 0.06), and klotho levels (<i>P</i> = 0.02). In conclusion, the early refeeding period was characterized by a decrease in markers of catabolism, whereas the later phase was characterized by an increase in anabolic markers. We suggest that IGF-1, UCR, and klotho may be used as markers of reversal of catabolism and shift toward anabolism in patients with severe malnutrition.<b>NEW & NOTEWORTHY</b> We provide a comprehensive temporal characterization of changes in biochemical markers of glucose homeostasis, GH-IGF-1 axis activity, and adipose tissue, bone, and protein metabolism during refeeding of adolescents with anorexia nervosa. Although IGF-I levels increased continuously, other markers showed a biphasic pattern: an early decrease in catabolic markers, followed by an increase in anabolic markers later during hospitalization. IGF-1, urea/creatinine ratio, and klotho emerged as potential clinical biomarkers of catabolic to anabolic transition in patients with severe malnutrition.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E845-E855"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966207","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":"Urinary exosomes exacerbate diabetic kidney disease by promoting NLRP3 inflammasome activation via the microRNA-516b-5p/SIRT3/AMPK pathway.","authors":"Haiying Zhang, Yubo Jiang, Jun Song, Shaoqing Wang, Jianhong Lu, Fuxin Wei, Xiu Li","doi":"10.1152/ajpendo.00527.2024","DOIUrl":"10.1152/ajpendo.00527.2024","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus. Urinary exosomal miRNAs play a prominent regulatory role in the pathogenesis of DKD, but the potential mechanisms remain largely unknown. Our research was designed to explain the pathogenesis of urine-derived exosomal microRNA-516b-5p (miR-516b-5p) in the DKD development. Urine-derived exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Immunofluorescence staining was used to detect cellular internalization. Quantitative real time-polymerase chain reaction (qRT-PCR) analysis was performed to measure the levels of miR-516b-5p and SIRT3. The secretion of inflammatory cytokines and Caspase-1 activity were evaluated via ELISA and flow cytometry, respectively. Expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome markers and genes associated with the SIRT3/AMPK signaling pathway were measured using Western blot. Bioinformatics tools and dual-luciferase reporter gene assay were used to confirm the correlation between miR-516b-5p and SIRT3. Blood glucose and renal function indexes were determined by the corresponding commercial kits. Hematoxylin and eosin (H&E) staining was exploited to examine the renal pathological changes. MiR-516b-5p was memorably upregulated in HKB-20 cells exposed to DKD-Exo. DKD-Exo introduction led to an increase in Caspase-1 activity, promoted inflammatory response and NLRP3 inflammasome activity, and inactivation of SIRT3/AMPK signaling pathway, which was partially reversed by silencing miR-516b-5p. SIRT3 was identified as a target gene of miR-516b-5p. SIRT3 overexpression reversed the influences of DKD-Exo and miR-516b-5p mimic. In the in vivo model, DKD-Exo exacerbated streptozotocin (STZ)-induced kidney injury through promoting inflammatory response and activating the NLRP3 inflammasome. Urinary exosomal miR-516b-5p plays a key role in DKD by promoting inflammatory response and activating the NLRP3 inflammasome through the SIRT3/AMPK pathway.<b>NEW & NOTEWORTHY</b> Urinary exosomal miR-516b-5p plays a key role in diabetic kidney disease (DKD) by promoting inflammatory response and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation through the SIRT3/AMPK pathway.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E911-E923"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959922","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":"FOXM1 cooperates with ERα to regulate functional β-cell mass.","authors":"Guihong Peng, Elham Mosleh, Andrew Yuhas, Kay Katada, Devi Kasinathan, Christopher Cherry, Maria L Golson","doi":"10.1152/ajpendo.00438.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00438.2024","url":null,"abstract":"<p><p>The transcription factor forkhead box (FOX)M1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing a constitutively active form of FOXM1 (FOXM1*) in β-cells increases β-cell function, proliferation, and mass in male mice. However, in contrast to what is observed in males, we demonstrate here that in female mice expression of FOXM1* in β-cells does not affect β-cell proliferation or glucose tolerance. Similarly, FOXM1* transduction of male but not female human islets enhances insulin secretion in response to elevated glucose. We therefore examined the mechanism behind this sexual dimorphism. Estrogen contributes to diabetes susceptibility differences between males and females, and estrogen receptor (ER)α is the primary mediator of β-cell estrogen signaling. Moreover, in breast cancer cells, ERα and FOXM1 work together to drive gene expression. We therefore examined whether FOXM1 and ERα functionally interact in β-cells. FOXM1* rescued elevated fasting glucose, glucose intolerance, and homeostatic model assessment of β-cell function (HOMA-B) in female mice with a β-cell-specific ERα deletion. Furthermore, in the presence of estrogen, the FOXM1 and ERα cistromes exhibit significant overlap in βTC6 β-cells. In addition, FOXM1 and ERα binding sites frequently occur in complex enhancers co-occupied by other islet transcription factors. These data indicate that FOXM1 and nuclear ERα cooperate to regulate β-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.<b>NEW & NOTEWORTHY</b> Here we investigate why the effects of increasing FOXM1 activity in β-cells observed in male mice are not seen in female mice. ERα likely collaborates with FOXM1 and other transcription factors to enhance gene expression related to β-cell function. Higher estrogen levels in females may contribute to their increased insulin secretion and the more severe consequences of losing transcription factors like FOXM1 in males. Overall, these findings shed light on sex differences in diabetes susceptibility.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E804-E821"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953477","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":"Low-frequency ultrasound reverses insulin resistance and diabetes-induced changes in the muscle transcriptome in aged mice.","authors":"Erik D Marchant, Ekta Singh, Sanjay Kureel, Brandon Blair, Hanna Kalenta, Zachary D Von Ruff, Korri S Weldon, Zhao Lai, Michael P Sheetz, Blake B Rasmussen","doi":"10.1152/ajpendo.00470.2024","DOIUrl":"10.1152/ajpendo.00470.2024","url":null,"abstract":"<p><p>The risk for developing insulin resistance and type II diabetes increases with age. Although lifestyle factors contribute to age-related insulin resistance, aging itself independently reduces insulin sensitivity, partially via an increase in inflammation and cellular senescence. Low-frequency ultrasound (LFU) has been shown to rejuvenate senescent cells and to reduce the proinflammatory senescence-associated secretory phenotype. Because diabetes is more common in aged individuals, there is an increased need to develop effective therapeutics for aged individuals with this condition. This study investigated the effects of LFU treatment on muscle function, blood glucose control, and skeletal muscle gene expression in aged, insulin-resistant, and diabetic mice. Insulin resistance was induced via a high-fat, high-sucrose (HFHS) diet, and diabetes was induced via an HFHS diet plus a low dose of streptozotocin. Insulin-resistant and diabetic mice exhibited impaired glucose metabolism and physical function, as well as an altered transcriptomic profile in skeletal muscle, indicating an increase in inflammation and an immune response. LFU treatment reversed much of the transcriptomic changes that occurred with insulin resistance and diabetes but had no effect on blood glucose control or physical function. LFU demonstrates potential as a noninvasive therapy for reducing inflammation and altering immune cell function in skeletal muscle in insulin-resistant and diabetic populations.<b>NEW & NOTEWORTHY</b> This study introduces low-frequency ultrasound (LFU) as a novel, noninvasive therapy that attenuates insulin resistance- and diabetes-induced transcriptional changes in aged skeletal muscle. LFU primarily reduced inflammatory and immune-related gene expression, potentially by promoting a shift toward an anti-inflammatory (M2) macrophage profile. These findings suggest that LFU may target underlying inflammatory mechanisms of insulin resistance and diabetes in aging muscle.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E899-E910"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963500","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":"Modulation of liver lipid metabolic pathways by central nervous system ER stress.","authors":"Han Rae Kim, Parisa Tabiatnejad, Hovhannes Arestakesyan, Colin N Young","doi":"10.1152/ajpendo.00392.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00392.2024","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD), considered as the hepatic manifestation of metabolic syndrome, can increase the risk for cardiometabolic diseases. Accumulating reports have implicated the central nervous system in MASLD pathogenesis, specifically endoplasmic reticulum (ER) stress in subfornical organ (SFO) to hypothalamic paraventricular nucleus (PVN) projecting neurons (SFO→PVN). Here, we investigated how ER stress in this neural circuit influences hepatic lipid regulatory pathways that may contribute to MASLD development during obesity. Hepatic steatosis was elicited by feeding C57BL/6J male mice a high-fat diet for 11 wk. Intersectional viral targeting was used to inhibit ER stress in SFO→PVN neurons to examine the contribution of ER stress in this circuit to hepatic lipid acquisition and disposal genes during obesity. Inhibition of ER stress in SFO→PVN neurons of obese mice resulted in a reduction in hepatic triglycerides and lipid acquisition genes that was paralleled by a reduction in liver tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Moreover, hepatic tyrosine hydroxylase expression was positively correlated with lipid acquisition but not disposal pathways. These results indicate that ER stress in SFO→PVN neurons may contribute to MASLD through sympathetic nervous system influences, primarily on hepatic lipid acquisition.<b>NEW & NOTEWORTHY</b> Endoplasmic reticulum stress in SFO→PVN neurons modulates hepatic lipid acquisition and disposal pathways during obesity-induced hepatic steatosis. Hepatic tyrosine hydroxylase levels are positively correlated with liver triglyceride levels and lipid acquisition pathway-related genes in diet-induced obese animals.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E833-E844"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957271","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":"<i>BRCA1</i> influences whole body metabolism in humanized mice.","authors":"Stacey Hembruff, Alexander Dekonenko, John P Thyfault, Mihaela E Sardiu, Michael P Washburn, Samuel G Mackintosh, Stephanie D Byrum, Roy A Jensen, Lisa M Harlan-Williams","doi":"10.1152/ajpendo.00222.2024","DOIUrl":"10.1152/ajpendo.00222.2024","url":null,"abstract":"<p><p>The role of <i>BRCA1</i> in cellular metabolism is not fully characterized and what we do understand has been primarily demonstrated in vitro. Our studies aimed to characterize the role of <i>BRCA1</i> in metabolic pathways in a whole body system. In vivo studies using C57BL/6 wild-type and transgenic humanized <i>BRCA1</i> mice demonstrate the effect of human <i>BRCA1</i> on the whole body metabolic phenotype and start to elucidate the mechanism by which this occurs. Promethion metabolic chambers and glucose tolerance tests measured a number of metabolic outputs of male and female mice that were either wild-type (normal mouse <i>Brca1</i> gene) or humanized <i>BRCA1</i> mice (knockout <i>Brca1</i>/knock-in human <i>BRCA1</i> gene). Humanized <i>BRCA1</i> mice are more lean, hyperactive, display higher energy expenditure, and demonstrate a sexual dimorphism in lean mass and glucose tolerance when compared with wild-type mice on the same genetic background. To begin to elucidate the mechanisms behind the observed metabolic phenotype, we performed mass spectrometry, SuperArray, and Western blot analysis using skeletal muscle, a metabolic organ that significantly impacts energy metabolism. Proteomic and genomic analysis revealed changes in a number of metabolic pathways that may be implicated in the observed whole body metabolic phenotype. We concluded that substituting <i>BRCA1</i> for <i>Brca1</i> in an in vivo model altered the overall metabolic profile of humanized <i>BRCA1</i> mice. Thus, the <i>Brca1/BRCA1</i> gene appears to have a significant impact on metabolic pathways, and these effects differ from mouse to human.<b>NEW & NOTEWORTHY</b> This is the first in vivo evidence demonstrating the complex effects of <i>BRCA1</i> expression in whole body metabolism.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E979-E993"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956245","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":"Follicular helper T cells in Graves' disease: pathogenic mechanisms and therapeutic implications.","authors":"Zhengrong Jiang, Linghong Huang, Lijun Chen, Huiyao Cai, Huibin Huang","doi":"10.1152/ajpendo.00023.2025","DOIUrl":"10.1152/ajpendo.00023.2025","url":null,"abstract":"<p><p>Graves' disease (GD) is a specific autoimmune disorder that primarily affects the thyroid gland, leading to thyrotoxicosis and potentially accompanied by extrathyroidal manifestations such as Graves' ophthalmopathy and pretibial myxedema. Its pathogenesis involves the abnormal proliferation of autoreactive B cells, which subsequently produce autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR), resulting in excessive secretion of thyroid hormones. Helper T cells (Th cells) play a significant role in this process. In recent years, follicular helper T cells (Tfh cells) have been identified as a novel subset of Th cells, primarily residing in the germinal centers (GCs) of lymphoid organs and in peripheral blood. Tfh cells facilitate B cell development and antibody production, thus playing a crucial role in the pathogenesis of GD. Their aberrant proliferation and function may lead to the production of autoantibodies and pathological processes such as tissue damage. This review summarizes the latest advancements in the biology of Tfh cells and their role in GD, exploring their potential as therapeutic targets, thereby providing new insights into the pathogenesis and treatment of GD.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E952-E961"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966609","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":"SGLT2 inhibitors use in kidney disease: what did we learn?","authors":"Munaza M Akunjee, Shikha G Khosla, Eric S Nylen, Sabyasachi Sen","doi":"10.1152/ajpendo.00034.2025","DOIUrl":"10.1152/ajpendo.00034.2025","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m² with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. <i>Annu Rev Med</i> 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E856-E868"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962061","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":"The metabolically protective energy expenditure increase of <i>Pik3r1</i>-related insulin resistance is not explained by Ucp1-mediated thermogenesis.","authors":"Ineke Luijten, Ami Onishi, Eleanor J McKay, Tore Bengtsson, Robert K Semple","doi":"10.1152/ajpendo.00449.2024","DOIUrl":"10.1152/ajpendo.00449.2024","url":null,"abstract":"<p><p>Human SHORT syndrome is caused by dominant negative human <i>PIK3R1</i> mutations that impair insulin-stimulated phosphoinositide 3-kinase (PI3K) activity. This produces severe insulin resistance (IR) and often reduced adiposity, commonly described as lipodystrophy. However, unlike human primary lipodystrophies, SHORT syndrome does not feature fatty liver or dyslipidemia. <i>Pik3r1^Y657*^/WT</i> (<i>Pik3r1^Y657*</i>) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure on high-fat feeding. We have hypothesized that this increased energy expenditure explains protection from lipotoxicity and suggested that understanding its mechanism may offer novel approaches to mitigating the metabolic syndrome. We set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure in <i>Pik3r1</i>-related IR. Male and female <i>Pik3r1^Y657*</i> mice challenged with a 45% fat diet for 3 wk at 21°C showed reduced metabolic efficiency not explained by changes in food intake or physical activity. No changes were seen in thermoregulation, assessed by thermal imaging and a modified Scholander protocol. Ucp1-dependent thermogenesis, assessed by norepinephrine-induced oxygen consumption, was also unaltered. Housing at 30°C did not alter the metabolic phenotype of male <i>Pik3r1^Y657*</i> mice but led to lowered physical activity in female <i>Pik3r1^Y657*</i> mice compared with controls. Nevertheless, these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30°C was similar in <i>Pik3r1^Y657*</i> and WT mice. We conclude that the likely metabolically protective \"energy leak\" in Pik3r1-related IR is not caused by Ucp1-mediated brown adipose tissue (BAT) hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non-Ucp1-mediated futile cycling.<b>NEW & NOTEWORTHY</b> Understanding how <i>Pik3r1^Y657*</i> mice and humans are protected from lipotoxicity despite insulin resistance may suggest new ways to mitigate metabolic syndrome. We find reduced metabolic efficiency in <i>Pik3r1^Y657*</i> mice but no differences in locomotion, thermoregulation, or Ucp1-dependent thermogenesis. The protective higher energy expenditure in Pik3r1-related insulin resistance has an alternative, likely metabolic, explanation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E743-E755"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727498","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}