American journal of physiology. Endocrinology and metabolism最新文献

{"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":"https://doi.org/10.1152/ajpendo.00449.2024","url":null,"abstract":"<p><p>Human SHORT syndrome is caused by dominant negative human PIK3R1 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 dyslipidaemia. <i>Pik3r1^Y657*/WT</i> (Pik3r1^Y657*) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure on high fat feeding. We have hypothesised 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 Pik3r1-related IR. Male and female Pik3r1^Y657* mice challenged with a 45% fat diet for 3 weeks 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 Pik3r1^Y657* mice, but led to lowered physical activity in female Pik3r1^Y657* mice compared to controls. Nevertheless these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30°C was similar in Pik3r1^Y657* and WT mice. We conclude that the likely metabolically protective 'energy leak' in Pik3r1-related IR is not caused by Ucp1- mediated BAT hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non Ucp1-mediated futile cycling.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-28","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}

{"title":"GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons.","authors":"Jiayi Shen, Mengtian Wang, Guodong Pang, Yan Zhang, Jian Zhang, Yuyan Shi, Ji Liu, Cheng Zhan","doi":"10.1152/ajpendo.00528.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00528.2024","url":null,"abstract":"<p><p>Peripherally delivered glucagon-like peptide-1 (GLP-1)-based drugs suppress eating through their action in the brain. However, the specific neuronal mechanisms, especially their impacts on the orexigenic circuit, remain largely elusive. Neuropeptide Y (NPY) neurons in the nucleus tractus solitarius (NTS) are newly identified as orexigenic neurons with a potent eating-stimulating effect, but their responses to GLP-1 drugs are unknown. Through ex vivo electrophysiological recordings, we study the impacts of GLP-1 receptor (GLP-1R) agonist exendin-4 on NTS^NPY neurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTS^NPY neuronal activity via GABA_b receptors by augmenting presynaptic GABA release. We also explored the contribution of NTS^NPY neurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTS^NPY neurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTS^NPY neurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTS^NPY neurons that may be targeted by a GLP-1R agonist to suppress food intake, suggesting that this neuronal population has translational importance as a potential therapeutic target for obesity treatment.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699378","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":"Mammary tumor development induces perturbation of liver glucose metabolism with inflammation and fibrosis.","authors":"Anouk Charlot, Anthony Bringolf, Joris Mallard, Amélie Jaulin, Emilie Crouchet, Anne-Laure Charles, Delphine Duteil, Fabien Alpy, Catherine-Laure Tomasetto, Thomas F Baumert, Joffrey Zoll","doi":"10.1152/ajpendo.00498.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00498.2024","url":null,"abstract":"<p><p>Cancer cells rely on glycolysis and lactic fermentation for ATP production, inducing an abnormal glucose uptake in tumors. However, it is largely unknown whether the increased tumor glucose consumption affects overall body glucose homeostasis including perturbation of the liver glucose production pathways. The effect of mammary tumor development on liver metabolism pathway was examined by using a mouse model based on FVB/N wild-type (WT-SD) and FVB/N-Tg(MMTV-PyVT)634Mul/J mice (Tg-SD), who develop spontaneous mammary tumors. Blood and livers were analyzed for metabolic changes, by measuring histological staining, signaling and insulin sensitivity. Tg-SD mice developed mammary tumors with an average weight of 6g, and cancer development increased total food intake without impacting body weight gain. Tumor development did not affect blood glycemia and lactate levels but increased insulin and HOMA-IR index (p=0.06). In the liver, Tg-SD mice with tumors exhibited a decrease in glycogen content, and an increase in gluconeogenesis gene expression, as G6pc, Pgc1α and Foxo1 (p<0.05), as well as Pepck and Ldha (p<0.01). Moreover, the phosphorylation of AMPK and AKT was significantly decreased (respectively (p<0.01 and p<0.05)). Surprisingly, liver fibrosis was markedly increased in Tg mice (p<0.05) alongside elevated inflammatory gene expression, such as IL1β (p<0.01) or IL6 (p<0.05). Here we found that the development of non-metastatic mammary tumors using the MMTV-PyMT mouse model disrupts liver function through the development of inflammation, fibrosis and metabolic perturbation, including an increase in glucose production and insulin resistance. Finally, these observations unravel a previously unknown metabolic crosstalk between the tumors and the liver.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662039","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":"Dehydration-induced AVP stimulates glucagon release and ketogenesis.","authors":"Thomas G Hill, Linford J B Briant, Angela Kim, Yanling Wu, Patrik Rorsman, Ingrid Wernstedt Asterholm, Anna Benrick","doi":"10.1152/ajpendo.00505.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00505.2024","url":null,"abstract":"<p><p>Gliflozins, such as dapagliflozin, belong to a class of drugs that inhibit the sodium-glucose cotransporter 2. Gliflozins have been found to raise glucagon levels, a hormone secreted from pancreatic islet alpha-cells, which can trigger ketosis. However, the precise mechanisms through which gliflozins increase glucagon secretion remain poorly understood. Additionally, gliflozins induce osmotic diuresis, resulting in increased urine volume and plasma osmolality. In this study, we investigated the hypothesis that a compensatory increase in arginine-vasopressin (AVP) mediates dapagliflozin-induced increases in glucagon <i>in vivo</i>. We show that dapagliflozin does not increase glucagon secretion in the perfused mouse pancreas, neither at clinical nor at supra-clinical doses. In contrast, AVP potently increases glucagon secretion. <i>In vivo</i>, dapagliflozin increased plasma glucagon, osmolality, and AVP. An oral load with hypertonic saline amplified dapagliflozin-induced glucagon secretion. Notably, a similar increase in glucagon could also be elicited by dehydration, evoked by 24-hour water restriction. Conversely, blockade of vasopressin 1b receptor signaling, with either pharmacological antagonism or knockout of the receptor, resulted in reduced dapagliflozin-induced glucagon secretion in response to both dapagliflozin and dehydration. Lastly, blocking vasopressin 1b receptor signaling in a mouse model of type 1 diabetes diminished the glucagon-promoting and ketogenic effects of dapagliflozin. Collectively, our data suggest that AVP is an important regulator of glucagon release during both drug-induced and physiological dehydration.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656039","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 choice of diet is determinative for the manifestation of UCP1-dependent diet-induced thermogenesis.","authors":"Raman Ahluwalia, Ineke H N Luijten, Celso P B Sousa-Filho, G Ruda F Braz, Natasa Petrovic, Irina G Shabalina, Barbara Cannon, Jan Nedergaard","doi":"10.1152/ajpendo.00038.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00038.2025","url":null,"abstract":"<p><p>The existence of the phenomenon of diet-induced thermogenesis - and its possible mediation by UCP1 in brown adipose tissue - has long been, and is presently, an important metabolic controversy. Particularly, several recent studies have failed to observe the hallmark of the phenomenon: augmentation of diet-induced obesity in UCP1-ablated mice, thus further casting doubt on the possible importance of this thermogenesis for human metabolic control. However, scrutiny of the experimental details revealed important procedural differences between experiments that did not or did show this augmentation of diet-induced obesity. Particularly, there were notable differences between the commercial diets used (Research-Diets or Ssniff). We therefore tested to what degree these differences would suffice to explain the absence of a UCP1 effect. Wildtype mice fed Research-Diets high-fat diet became obese but UCP1-ablated mice became even more obese, as expected if UCP1-dependent diet-induced thermogenesis exists. Mice fed the Ssniff high-fat diet became less obese than those on the Research-Diets food - and, importantly, no effect of UCP1 ablation was seen. The result with the Research-Diets diet was fully due to differences in total fat mass and not explainable by differences in food intake. The two diets are different in carbohydrate (sucrose) and lipid (lard versus palm oil) composition and in texture and taste. Probably some of these factors explain the difference but the important conclusion is that when an appropriate diet was offered, the body weight manifestation of UCP1-dependent diet-induced thermogenesis was a reproducible phenomenon that may have significance also for human metabolic control.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646955","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":"Six-hour hypoxia induced protein degradation in <i>M. gastrocnemius</i> of 24-day-old mice by activating FOXO1 and suppressing AKT-mTORC1.","authors":"Jingyi Song, Marcel Jaklofsky, Claudia Carmone, Vincent de Boer, Niels Wever, Jaap Keijer, Sander Grefte","doi":"10.1152/ajpendo.00508.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00508.2024","url":null,"abstract":"<p><p>Long-term hypoxia has been associated with skeletal muscle atrophy, including increased protein degradation over protein synthesis. This contrasts sharply with muscle hypertrophy and net protein synthesis occurring in developing skeletal muscle of young mice. Here, we aimed to understand the impact of acute, physiologically plausible environmental hypoxia on muscle proteostasis of the <i>M. gastrocnemius</i> of young mice. Fasted prepubertal, 24-day-old male B6JRccHsd(B6J)-<i>Nnt⁺</i>/Wuhap mice with similar body weight and lean mass were exposed to normobaric hypoxia (12% O₂) or normoxia (20.9% O₂) for 6 hours. The transcriptome (n=12) and protein (n=6) response of the <i>M. gastrocnemius</i> were analyzed. A hypoxic response of <i>M. gastrocnemius</i> was confirmed by increased expression of HIF1 (<i>Ankrd37</i> and <i>Ddit4</i>) and forkhead box-O (FOXO) 1 (<i>Depp1</i> and <i>Ddit4</i>) target genes. RNA-Seq analysis revealed that hypoxia activated FOXO signaling, which was confirmed by increased FOXO1 protein levels and decreased p-AKT/AKT ratio. Detailed mapping of the FOXO1 pathway suggests a strong FOXO1-mediated hypoxic effect on protein degradation and synthesis. A central role of <i>Atf4</i> is suggested by the hypoxic-dependent positive correlations with FOXO1, FBXO32, <i>Depp1, Eif4ebp1</i> and <i>Ddit4</i>. Further analyses showed increased FBXO32, which positively correlated with FOXO1, and decreased p-S6K/S6K and p-4E-BP1/4E-BP1 ratios. Our results showed for the first time that a 6-hour exposure to 12% O₂ normobaric hypoxia in 24-day-old mice activates FOXO1 signaling in <i>M. gastrocnemius</i>, resulting in decreased protein synthesis and increased protein degradation most likely via reduced energy availability, which may be relevant for infant air or high altitude traveling.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646953","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":"Plasma complement system markers and their association with cardiometabolic risk factors: an ethnic comparison of White European and Black African men.","authors":"Reuben M Reed, Wioleta M Zelek, B Paul Morgan, Gráinne Whelehan, Sam Lockhart, Stephen O'Rahilly, Oliver C Witard, Martin B Whyte, Louise M Goff","doi":"10.1152/ajpendo.00419.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00419.2024","url":null,"abstract":"<p><p>Populations of Black African (BA) ancestry are disproportionately affected by cardiometabolic diseases, possibly due to dysregulation of the complement system. This study aimed to determine 1) relationships between fasting complement markers and cardiometabolic risk in BA and White European (WE) men, and 2) whether postprandial complement response differs by ethnicity. Eighty-eight BA and 97 WE men (age=44.4 [42.0-47.6] years, BMI=29.2±4.5 kg/m²) were assessed for fasting plasma complement markers and cardiometabolic risk factors. A second cohort (<i>n</i>=20 men, 10 BA) (age=31.0±1.1 years, BMI=27.1 [26.0-28.6] kg/m²) men underwent a moderate-to-high-fat feeding protocol to measure postprandial plasma complement, serum insulin, plasma glucose, TAG and non-esterified fatty acids. C4 and Factor D were lower, and iC3b was higher, in BA compared with WE men. C3 and C4 were strongly associated with all adiposity markers in both ethnicities, but the WE cohort showed stronger associations between C3 and subcutaneous adipose tissue, C5 and WC, and iC3b and visceral adipose tissue compared with BA. C3 was associated with all cardiometabolic risk factors in both ethnicities. Associations between C5 and cholesterol, C4 and TAG, and TCC and (both total and LDL)-cholesterol were only observed in the WE cohort. There was a trend towards ethnic differences in postprandial Factor D (<i>P</i>=0.097) and iC3b (<i>P</i>=0.085). The weaker associations between the complement system markers with adiposity and lipid profiles in BA compared with WE men suggest ethnic differences in the determinants of complement production and activation, whereby adipose tissue may play a less important role in BA men.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565782","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":"Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.","authors":"Maria F Pino, Pieter Dijkstra, Katie L Whytock, Cheehoon Ahn, Gongxin Yu, James A Sanford, Josh Hansen, Chelsea Hutchinson, Marina Gritsenko, Paul Piehowski, Joshua N Adkins, Elvis A Carnero, Stuart Sealfon, Elena Zaslavsky, Venugopalan Nair, Steve R Smith, Lauren M Sparks","doi":"10.1152/ajpendo.00339.2024","DOIUrl":"10.1152/ajpendo.00339.2024","url":null,"abstract":"<p><p>White adipose tissue (WAT) plays a significant role in whole body energy homeostasis, and its excess typifies obesity. In addition to WAT quantity, perturbations in the basic cellular processes of WAT (i.e., quality) are also associated with obesity and metabolic disease. Exercise training alleviates metabolic perturbations associated with obesity; however, the underlying molecular mechanisms that drive these metabolic adaptations in WAT are not well described. Abdominal subcutaneous WAT biopsies were collected after an acute bout of exercise (1 day after) at baseline and following 3 wk of supervised aerobic training in sedentary overweight women (<i>n</i> = 6) without alterations in body weight and fat mass. RNA-seq, global proteomics, and phosphoproteomics in WAT revealed training-induced changes in 1,527 transcripts, 154 proteins, and 144 phosphosites, respectively. Training decreased abundance of transcripts and proteins involved in inflammation and components of the extracellular matrix and increased abundance of transcripts and proteins related to fatty acid esterification and lipolysis. In summary, short-term aerobic training significantly reduces local inflammation and increases lipid metabolism in WAT of sedentary overweight women-independent of alterations in body and fat mass. As such, some of the health benefits of aerobic training may occur through molecular alterations in WAT (i.e., enhanced quality) rather than a sheer reduction in WAT quantity.<b>NEW & NOTEWORTHY</b> This is the first study to utilize a multiomic (RNAseq, proteomics, and phosphoproteomics) approach to investigate molecular adaptations in WAT after a short-term intervention in sedentary overweight women. We show that supervised aerobic training reduces molecular markers of inflammation and proteins regulating ECM and increases abundance of transcripts and proteins involved in lipolysis and fatty acid re-esterification, indicating that molecular adaptations in WAT occur independent of alterations in body weight or fat mass.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E478-E492"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397764","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":"A novel soluble guanylate cyclase activator, avenciguat, in combination with empagliflozin, protects against renal and hepatic injury in diabetic <i>db/db</i> mice.","authors":"Nisha Sharma, Wenjin Liu, Xiao-Qing E Tsai, Zhou Wang, Connor Outtrim, Anna Tang, Michael P Pieper, Glenn A Reinhart, Yufeng Huang","doi":"10.1152/ajpendo.00254.2024","DOIUrl":"10.1152/ajpendo.00254.2024","url":null,"abstract":"<p><p>Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide/soluble guanylate cyclase (sGC) signaling. This study aimed to determine whether the administration of a novel sGC activator avenciguat alone or in combination with an SGLT2 inhibitor could slow the progression of renal and liver fibrosis in the type 2 diabetic and uninephrectomized <i>db/db</i> mouse model. Experiment groups included normal controls, untreated <i>db/db</i> mice terminated at 12 and 18 wk of age, and <i>db/db</i> mice treated with either one of two doses of avenciguat alone, empagliflozin (Empa) alone, or a combination of both from <i>weeks 12</i> to <i>18</i> of age. Untreated <i>db/db</i> mice exhibited obesity, hyperglycemia, elevated levels of HbA1c and triglycerides (TG), and developed progressive albuminuria, glomerulosclerosis, fatty liver, and liver fibrosis between <i>weeks 12</i> and <i>18</i> of age, accompanied by increased renal and liver production of fibronectin, type-IV collagen, laminin, and increased oxidative stress markers. Avenciguat had no effect on body weight but reduced both blood HbA1c and TG levels, whereas Empa reduced HbA1c but not TG levels as compared with untreated <i>db/db</i>. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high doses in combination with Empa, further lowered these progression markers compared with baseline measurements. These results suggested that either avenciguat alone or in combination with Empa is therapeutic. Avenciguat in combination with Empa shows promise in halting the progression of diabetic complications.<b>NEW & NOTEWORTHY</b> Whether combining an sGC activator with an SGLT2 inhibitor could better control diabetes-associated oxidative stress and NO-cGMP signal deficiency has not yet been explored. Using the type 2 diabetic <i>db/db</i> mouse model, this study underscores the sGC activator avenciguat as a novel therapy for diabetic nephropathy and liver injury beyond sGLT2 inhibitors. It also highlights the need for further investigation into the combined effects of these two treatments in managing diabetic complications.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E362-E376"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187965","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":"Placenta <i>hIGF1</i> nanoparticle treatment in guinea pigs mitigates FGR-associated fetal sex-dependent effects on liver metabolism-related signaling pathways.","authors":"Baylea N Davenport, Alyssa Williams, Timothy R H Regnault, Helen N Jones, Rebecca L Wilson","doi":"10.1152/ajpendo.00440.2024","DOIUrl":"10.1152/ajpendo.00440.2024","url":null,"abstract":"<p><p>Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, nonalcoholic fatty liver diseases, and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency and fetal weight were significantly improved following three administrations of a nonviral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (<i>gestational day 35</i>) until <i>gestational day 52</i>. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (<i>hIGF1</i>) in placenta trophoblast. Fetal liver tissue was collected near-term at <i>gestational day 60</i>. Fetal sex-specific differences in liver gene and protein expression of profibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental <i>hIGF1</i> nanoparticle treatment. Increased plasma bilirubin, an indirect measure of hepatic activity, was also demonstrated with placental <i>hIGF1</i> nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.<b>NEW & NOTEWORTHY</b> A placenta-specific nonviral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later life. This knowledge may have implications toward removing predispositions that increase the risk of metabolic diseases, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease in later life.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E395-E409"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187974","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}