Denis P Blondin, François Haman, Tracy M Swibas, Sophie Hogan-Lamarre, Lauralyne Dumont, Jolan Guertin, Gabriel Richard, Quentin Weissenburger, Kerry L Hildreth, Irene Schauer, Shelby Panter, Liza Wyland, André C Carpentier, Yubin Miao, Jiayuan Shi, Elizabeth Juarez-Colunga, Wendy M Kohrt, Edward L Melanson
{"title":"Brown adipose tissue metabolism in women is dependent on ovarian status.","authors":"Denis P Blondin, François Haman, Tracy M Swibas, Sophie Hogan-Lamarre, Lauralyne Dumont, Jolan Guertin, Gabriel Richard, Quentin Weissenburger, Kerry L Hildreth, Irene Schauer, Shelby Panter, Liza Wyland, André C Carpentier, Yubin Miao, Jiayuan Shi, Elizabeth Juarez-Colunga, Wendy M Kohrt, Edward L Melanson","doi":"10.1152/ajpendo.00077.2024","DOIUrl":"10.1152/ajpendo.00077.2024","url":null,"abstract":"<p><p>In rodents, loss of estradiol (E<sub>2</sub>) reduces brown adipose tissue (BAT) metabolic activity. Whether E<sub>2</sub> impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (<i>n</i> = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m<sup>2</sup>) and postmenopausal (<i>n</i> = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m<sup>2</sup>) women at room temperature and during acute cold exposure using [<sup>11</sup>C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[<sup>18</sup>F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (<i>n</i> = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m<sup>2</sup>) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min<sup>-1</sup>) and postmenopausal women (0.63 ± 0.28 min<sup>-1</sup>). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min<sup>-1</sup>, <i>P</i> = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g<sup>-1</sup>·min<sup>-1</sup>, <i>P</i> < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min<sup>-1</sup> to 0.91 ± 0.41 min<sup>-1</sup>) to that observed in postmenopausal women (0.91 ± 0.63 min<sup>-1</sup>). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.<b>NEW & NOTEWORTHY</b> In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E588-E601"},"PeriodicalIF":4.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140108797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew E Libby, Claudia M Solt, Matthew R Jackman, Vanessa D Sherk, Rebecca M Foright, Ginger C Johnson, Thi-Tina Nguyen, Matthew J Breit, Nicholas Hulett, Michael C Rudolph, Paul A Roberson, Elizabeth A Wellberg, Purevsuren Jambal, Rebecca L Scalzo, Janine Higgins, T Rajendra Kumar, Margaret E Wierman, Zhaoxing Pan, Kartik Shankar, Dwight J Klemm, Kerrie L Moreau, Wendy M Kohrt, Paul S MacLean
{"title":"Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.","authors":"Andrew E Libby, Claudia M Solt, Matthew R Jackman, Vanessa D Sherk, Rebecca M Foright, Ginger C Johnson, Thi-Tina Nguyen, Matthew J Breit, Nicholas Hulett, Michael C Rudolph, Paul A Roberson, Elizabeth A Wellberg, Purevsuren Jambal, Rebecca L Scalzo, Janine Higgins, T Rajendra Kumar, Margaret E Wierman, Zhaoxing Pan, Kartik Shankar, Dwight J Klemm, Kerrie L Moreau, Wendy M Kohrt, Paul S MacLean","doi":"10.1152/ajpendo.00400.2023","DOIUrl":"10.1152/ajpendo.00400.2023","url":null,"abstract":"<p><p>Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E<sub>2</sub>), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E<sub>2</sub> in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E<sub>2</sub> and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (<i>P</i> < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.<b>NEW & NOTEWORTHY</b> We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E626-E639"},"PeriodicalIF":4.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandra Galli, Stefania Moretti, Nevia Dule, Eliana Sara Di Cairano, Michela Castagna, Paola Marciani, Cristina Battaglia, Federico Bertuzzi, Ida Pastore, Paolo Fiorina, Stefano La Rosa, Alberto Davalli, Franco Folli, Carla Perego
{"title":"Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis","authors":"Alessandra Galli, Stefania Moretti, Nevia Dule, Eliana Sara Di Cairano, Michela Castagna, Paola Marciani, Cristina Battaglia, Federico Bertuzzi, Ida Pastore, Paolo Fiorina, Stefano La Rosa, Alberto Davalli, Franco Folli, Carla Perego","doi":"10.1152/ajpendo.00069.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00069.2024","url":null,"abstract":"Pancreatic endocrine cells employ a sophisticated system of paracrine and autocrine signals to synchronize their activities, including glutamate which controls hormone release and β-cell viability by acting on glutamate receptors expressed by endocrine cells. We here investigate whether alteration of the Excitatory Amino Acid Transporter 2 (EAAT2), the major glutamate clearance system in the islet, may occur in type 2 diabetes mellitus (T2DM) and contribute to β-cell dysfunction. Increased EAAT2 intracellular localization was evident in islets of Langerhans from T2DM subjects as compared with healthy control subjects, despite similar expression levels. Chronic treatment of islets from healthy donors with high glucose concentrations led to the transporter internalization in vesicular compartments and reduced [H<sup>3</sup>]-D-glutamate uptake (65±5% inhibition), phenocopying the findings in T2DM pancreatic sections. The transporter relocalization was associated to decreased Akt phosphorylation protein levels, suggesting an involvement of the PI3K/Akt pathway in the process. In line with this, PI3K inhibition by 100 µM LY294002 treatment in human and clonal β-cells, caused the transporter relocalization in intracellular compartments and significantly reduced the glutamate uptake compared to control conditions, suggesting that hyperglycemia changes the trafficking of the transporter to the plasma membrane. Upregulation of the glutamate transporter upon treatment with the antibiotic ceftriaxone rescued hyperglycemia-induced β-cells dysfunction and death. Our data underscore the significance of EAAT2 in regulating islet physiology and provide a rationale for potential therapeutic targeting of this transporter to preserve β-cell survival and function in diabetes.","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"40 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832669","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":"Larsucosterol: endogenous epigenetic regulator for treating chronic and acute liver diseases.","authors":"Yaping Wang, Jenna Ren, Shunlin Ren","doi":"10.1152/ajpendo.00406.2023","DOIUrl":"10.1152/ajpendo.00406.2023","url":null,"abstract":"<p><p>Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The administration of larsucosterol has demonstrated a reduction in lipid accumulation within hepatocytes and the attenuation of inflammatory responses induced by lipopolysaccharide (LPS) and TNFα in macrophages, alleviating LPS- and acetaminophen (ATMP)-induced multiple organ injury, and decreasing mortalities in animal models. Results from <i>phase 1</i> and <i>2</i> clinical trials have shown that larsucosterol has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that larsucosterol is a promising candidate for treating alcohol-associated hepatitis with positive results from a <i>phase 2a</i> clinical trial, and for metabolic dysfunction-associated steatohepatitis (MASH) from a <i>phase 1b</i> clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of larsucosterol. Furthermore, we elucidate the pathophysiological pathways of metabolic dysfunction-associated steatotic liver diseases (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of larsucosterol in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E577-E587"},"PeriodicalIF":4.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139911855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ioannis I. Lazaridis, Angela J.T. Bosch, Lena Keller, Andy J.Y. Low, Jeanne Tamarelle, Seraina O. Moser, Denise V. Winter, Cristina Gómez, Caspar J. Peterson, Romano Schneider, Marko Kraljevic, Alex Odermatt, Pascale Vonaesch, Ralph Peterli, Tarik Delko, Claudia Cavelti-Weder
{"title":"Metabolic outcomes in obese mice undergoing one-anastomosis gastric bypass (OAGB) with a long or a short biliopancreatic limb","authors":"Ioannis I. Lazaridis, Angela J.T. Bosch, Lena Keller, Andy J.Y. Low, Jeanne Tamarelle, Seraina O. Moser, Denise V. Winter, Cristina Gómez, Caspar J. Peterson, Romano Schneider, Marko Kraljevic, Alex Odermatt, Pascale Vonaesch, Ralph Peterli, Tarik Delko, Claudia Cavelti-Weder","doi":"10.1152/ajpendo.00327.2023","DOIUrl":"https://doi.org/10.1152/ajpendo.00327.2023","url":null,"abstract":"One-anastomosis gastric bypass (OAGB) has gained importance as a safe and effective operation to treat morbid obesity. It is not known whether a long biliopancreatic limb (BPL) in OAGB surgery compared to a short BPL results in beneficial metabolic outcomes. 5-week-old male C57BL/6J mice fed a high-fat diet for 8 weeks underwent OAGB surgery with defined short and long BPL lengths, or sham surgery combined with caloric restriction. Weight loss, glucose tolerance, obesity-related comorbidities, endocrine effects, gut microbiota and bile acids were assessed. Total weight loss was independent of the length of the BPL after OAGB surgery. However, a long BPL was associated with lower glucose-stimulated insulin on day 14, and an improved glucose tolerance on day 35 after surgery. A long BPL resulted in reduced total cholesterol. There were no differences in the resolution of metabolic dysfunction-associated steatotic liver disease and adipose tissue inflammation. Tendencies of an attenuated hypothalamic-pituitary-adrenal axis and aldosterone were present in the long BPL group. In OAGB-operated mice, we found an increase in primary conjugated bile acids (pronounced in long BPL) along with a loss in bacterial <i>Desulfovibrionaceae</i> and <i>Erysipelotrichaceae </i>and simultaneous increase in <i>Akkermansiaceae, Sutterellaceae </i>and <i>Enterobacteriaceae</i>. In sum, OAGB surgery with a long compared to a short BPL led to similar weight loss, but improved glucose metabolism, lipid and endocrine outcomes in obese mice, potentially mediated through changes in gut microbiota and related bile acids. Tailoring the BPL length in humans might help to optimize metabolic outcomes after bariatric surgery.","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"12 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617350","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}
Kaitlyn C. Stickel, Nikhil R. Shah, Emily T. Claeboe, Kara S. Orr, Amber L. Mosley, Emma H. Doud, Teri L. Belecky-Adams, Anthony J. Baucum
{"title":"Mechanisms of spinophilin-dependent pancreas dysregulation in obesity","authors":"Kaitlyn C. Stickel, Nikhil R. Shah, Emily T. Claeboe, Kara S. Orr, Amber L. Mosley, Emma H. Doud, Teri L. Belecky-Adams, Anthony J. Baucum","doi":"10.1152/ajpendo.00099.2023","DOIUrl":"https://doi.org/10.1152/ajpendo.00099.2023","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Ahead of Print. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"28 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617190","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}
Shaarav Ghose, Matthew Satariano, Saichidroopi Korada, Thomas Cahill, Raghav Shah, Rupesh Raina
{"title":"Advancements in Diabetic Kidney Disease Management: Integrating Innovative Therapies and Targeted Drug Development","authors":"Shaarav Ghose, Matthew Satariano, Saichidroopi Korada, Thomas Cahill, Raghav Shah, Rupesh Raina","doi":"10.1152/ajpendo.00026.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00026.2024","url":null,"abstract":"Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of diabetic individuals. Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common co-morbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. SGLT-2 inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including GLP-1 agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, Lixudebart, and tozorakimab, mesenchymal stem/stromal cell infusion, and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"100 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617353","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":"Corrigendum for Subramanian et al., volume 326, 2024, p. E182–E205","authors":"","doi":"10.1152/ajpendo.00278.2023_cor","DOIUrl":"https://doi.org/10.1152/ajpendo.00278.2023_cor","url":null,"abstract":"American Journal of Physiology-Endocrinology and Metabolism, Volume 326, Issue 4, Page E545-E545, April 2024. <br/>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599200","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":"Medium-Chain Triglycerides-Specific Appetite is Regulated by the β-oxidation of Medium-Chain Fatty Acids in the Liver","authors":"Tsugunori Maruyama, Sho Matsui, Ryosuke Kobayashi, Takuro Horii, Yasuo Oguri, Satoshi Tsuzuki, Takahiro Horie, Koh Ono, Izuho Hatada, Tsutomu Sasaki","doi":"10.1152/ajpendo.00031.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00031.2024","url":null,"abstract":"Most studies on fat appetite have focused on long-chain triglycerides (LCTs) due to their obesogenic properties. Medium-chain triglycerides (MCTs), conversely, exhibit anti-obesogenic effects; however, the regulation of MCTs intake remains elusive. Here, we demonstrate that mice can distinguish between MCTs and LCTs, and the specific appetite for MCTs is governed by hepatic β-oxidation. We generated liver-specific medium-chain acyl-CoA dehydrogenase (MCAD)-deficient (MCAD<sup>L-/-</sup>) mice and analyzed their preference for MCTs and LCTs solutions using glyceryl trioctanoate (C8-TG), glyceryl tridecanoate (C10-TG), corn oil, and lard oil in two-bottle choice tests conducted over 8 days. Additionally, we employed lick microstructure analyses to evaluate the palatability and appetite for MCTs and LCTs solutions. Finally, we measured the expression levels of genes associated with fat ingestion (<i>Galanin</i>, <i>Qrfp</i>, and <i>Nmu</i>) in the hypothalamus 2 h after oral gavage of fat. Compared to control mice, MCAD<sup>L-/-</sup> mice exhibited a significantly reduced preference for MCTs solutions, with no alteration in the preference for LCTs. Lick analysis revealed that MCAD<sup>L-/-</sup> mice displayed a significantly decreased appetite for MCTs solutions only, while the palatability of both MCTs and LCTs solutions remained unaffected. Hypothalamic <i>Galanin</i> expression in control mice was elevated by oral gavage of C8-TG but not by LCTs, and this response was abrogated in MCAD<sup>L-/-</sup> mice. In summary, our data suggest that hepatic β-oxidation is required for MCTs-specific appetite but not for LCTs-specific appetite. The induction of hypothalamic galanin upon MCTs ingestion, dependent on hepatic beta-oxidation, could be involved in the regulation of MCTs-specific appetite.","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"1212 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599194","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}
Lara Regina-Ferreira, Fernando Valdivieso-Rivera, Monara K.S.C. Angelim, Larissa Menezes dos Reis, Vanessa O. de Oliveira Furino, Joseane Morari, Lizandra Maia de Souza, Silvio R. Consoni, Carlos H. Sponton, Pedro M. Moraes Vieira, Licio A. Velloso
{"title":"Inhibition of Crif1 protects fatty acid-induced POMC neuron damage by increasing CPT-1 function","authors":"Lara Regina-Ferreira, Fernando Valdivieso-Rivera, Monara K.S.C. Angelim, Larissa Menezes dos Reis, Vanessa O. de Oliveira Furino, Joseane Morari, Lizandra Maia de Souza, Silvio R. Consoni, Carlos H. Sponton, Pedro M. Moraes Vieira, Licio A. Velloso","doi":"10.1152/ajpendo.00420.2023","DOIUrl":"https://doi.org/10.1152/ajpendo.00420.2023","url":null,"abstract":"Hypothalamic proopiomelanocortin neurons are sensors of signals that reflect the energy stores in the body. Inducing mild stress in proopiomelanocortin neurons protect them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling. Furthermore, the partial inhibition of Crif1 resulted in increased reactive oxygen species production, increased fatty acid oxidation, and reduced dependency on glucose for mitochondrial respiration. These changes were dependent on the activity of CPT-1. Thus, we identified a CPT-1-dependent metabolic shift towards greater utilization of fatty acids as substrates for respiration as the mechanism behind the protective effect of mild stress against palmitate-induced damage of proopiomelanocortin neurons.","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"70 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599197","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}