Pub Date : 2024-12-29DOI: 10.1016/j.metabol.2024.156125
María J. Vazquez , Silvia Daza-Dueñas , Inmaculada Velasco , Francisco Ruiz-Pino , María J. Sanchez-Tapia , María Manfredi-Lozano , Carmen Torres-Granados , Alexia Barroso , Juan Roa , Miguel A. Sánchez-Garrido , Carlos Dieguez , Alejandro Lomniczi , Rubén Nogueiras , Manuel Tena-Sempere
Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of Kiss1, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express Sirt1 mRNA. Reciprocal changes in hypothalamic SIRT1 content and Kiss1 expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced Kiss1 expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.
{"title":"Hypothalamic SIRT1-mediated regulation of the hormonal trigger of ovulation and its repression in energy deficit","authors":"María J. Vazquez , Silvia Daza-Dueñas , Inmaculada Velasco , Francisco Ruiz-Pino , María J. Sanchez-Tapia , María Manfredi-Lozano , Carmen Torres-Granados , Alexia Barroso , Juan Roa , Miguel A. Sánchez-Garrido , Carlos Dieguez , Alejandro Lomniczi , Rubén Nogueiras , Manuel Tena-Sempere","doi":"10.1016/j.metabol.2024.156125","DOIUrl":"10.1016/j.metabol.2024.156125","url":null,"abstract":"<div><div>Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of <em>Kiss1</em>, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express <em>Sirt1</em> mRNA. Reciprocal changes in hypothalamic SIRT1 content and <em>Kiss1</em> expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced <em>Kiss1</em> expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156125"},"PeriodicalIF":10.8,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-29DOI: 10.1016/j.metabol.2024.156126
Yi-Lin Chen , Jia You , Yu Guo , Yi Zhang , Bing-Ran Yao , Ji-Jing Wang , Shi-Dong Chen , Yi-Jun Ge , Liu Yang , Xin-Rui Wu , Bang-Sheng Wu , Ya-Ru Zhang , Qiang Dong , Jian-Feng Feng , Mei Tian , Wei Cheng , Jin-Tai Yu
Background and aims
Multimorbidity, the coexistence of multiple chronic diseases, is a rapidly expanding global health challenge, carrying profound implications for patients, caregivers, healthcare systems, and society. Investigating the determinants and drivers underlying multiple chronic diseases is a priority for disease management and prevention.
Method
This prospective cohort study analyzed data from the 53,026 participants in the UK Biobank from baseline (2006 to 2010) across 13.3 years of follow-up. Using Cox proportional hazards regression model, we characterized shared and unique associations across 38 incident outcomes (31 chronic diseases, 6 system mortality and all-cause mortality). Furthermore, ordinal regression models were used to assess the association between protein levels and multimorbidity (0–1, 2, 3–4, or ≥ 5 chronic diseases). Functional and tissue enrichment analysis were employed for multimorbidity-associated proteins. The upstream regulators of above proteins were identified.
Results
We demonstrated 972 (33.3 %) proteins were shared across at least two incident chronic diseases after Bonferroni correction (P < 3.42 × 10−7, 93.3 % of those had consistent effects directions), while 345 (11.8 %) proteins were uniquely linked to a single chronic disease. Remarkably, GDF15, PLAUR, WFDC2 and AREG were positively associated with 20–24 incident chronic diseases (hazards ratios: 1.21–3.77) and showed strong associations with multimorbidity (odds ratios: 1.33–1.89). We further identified that protein levels are explained by common risk factors, especially renal function, liver function, inflammation, and obesity, providing potential intervention targets. Pathway analysis has underscored the pivotal role of the immune response, with the top three transcription factors associated with proteomics being NFKB1, JUN and RELA.
Conclusions
Our results enhance the understanding of the biological basis underlying multimorbidity, offering biomarkers for disease identification and novel targets for therapeutic intervention.
{"title":"Identifying proteins and pathways associated with multimorbidity in 53,026 adults","authors":"Yi-Lin Chen , Jia You , Yu Guo , Yi Zhang , Bing-Ran Yao , Ji-Jing Wang , Shi-Dong Chen , Yi-Jun Ge , Liu Yang , Xin-Rui Wu , Bang-Sheng Wu , Ya-Ru Zhang , Qiang Dong , Jian-Feng Feng , Mei Tian , Wei Cheng , Jin-Tai Yu","doi":"10.1016/j.metabol.2024.156126","DOIUrl":"10.1016/j.metabol.2024.156126","url":null,"abstract":"<div><h3>Background and aims</h3><div>Multimorbidity, the coexistence of multiple chronic diseases, is a rapidly expanding global health challenge, carrying profound implications for patients, caregivers, healthcare systems, and society. Investigating the determinants and drivers underlying multiple chronic diseases is a priority for disease management and prevention.</div></div><div><h3>Method</h3><div>This prospective cohort study analyzed data from the 53,026 participants in the UK Biobank from baseline (2006 to 2010) across 13.3 years of follow-up. Using Cox proportional hazards regression model, we characterized shared and unique associations across 38 incident outcomes (31 chronic diseases, 6 system mortality and all-cause mortality). Furthermore, ordinal regression models were used to assess the association between protein levels and multimorbidity (0–1, 2, 3–4, or ≥ 5 chronic diseases). Functional and tissue enrichment analysis were employed for multimorbidity-associated proteins. The upstream regulators of above proteins were identified.</div></div><div><h3>Results</h3><div>We demonstrated 972 (33.3 %) proteins were shared across at least two incident chronic diseases after Bonferroni correction (P < 3.42 × 10<sup>−7</sup>, 93.3 % of those had consistent effects directions), while 345 (11.8 %) proteins were uniquely linked to a single chronic disease. Remarkably, GDF15, PLAUR, WFDC2 and AREG were positively associated with 20–24 incident chronic diseases (hazards ratios: 1.21–3.77) and showed strong associations with multimorbidity (odds ratios: 1.33–1.89). We further identified that protein levels are explained by common risk factors, especially renal function, liver function, inflammation, and obesity, providing potential intervention targets. Pathway analysis has underscored the pivotal role of the immune response, with the top three transcription factors associated with proteomics being NFKB1, JUN and RELA.</div></div><div><h3>Conclusions</h3><div>Our results enhance the understanding of the biological basis underlying multimorbidity, offering biomarkers for disease identification and novel targets for therapeutic intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156126"},"PeriodicalIF":10.8,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1016/j.metabol.2024.156114
Jeong-Su Park , Yuan-Qiang Ma , Feng Wang , Hwan Ma , Guoyan Sui , Nodir Rustamov , Minyeong Han , Yejin Son , Chun-Woong Park , Sang-Bae Han , Jin Tae Hong , Lak Shin Jeong , Jin Lee , Yoon Seok Roh
Background & aims
Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD.
Approach & results
A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4′-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects.
Conclusions
This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.
{"title":"A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution","authors":"Jeong-Su Park , Yuan-Qiang Ma , Feng Wang , Hwan Ma , Guoyan Sui , Nodir Rustamov , Minyeong Han , Yejin Son , Chun-Woong Park , Sang-Bae Han , Jin Tae Hong , Lak Shin Jeong , Jin Lee , Yoon Seok Roh","doi":"10.1016/j.metabol.2024.156114","DOIUrl":"10.1016/j.metabol.2024.156114","url":null,"abstract":"<div><h3>Background & aims</h3><div>Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD.</div></div><div><h3>Approach & results</h3><div>A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4′-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects.</div></div><div><h3>Conclusions</h3><div>This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156114"},"PeriodicalIF":10.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity.
Methods
A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators.
Results
Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [−4.81, −2.29]), fat mass (MD -2.95 kg, 95 %-CI [−4.11, −1.79]), and lean mass (MD -0.86 kg, 95 %-CI [−1.30, −0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass.
Conclusions
Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.
{"title":"Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis","authors":"Paschalis Karakasis , Dimitrios Patoulias , Nikolaos Fragakis , Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156113","DOIUrl":"10.1016/j.metabol.2024.156113","url":null,"abstract":"<div><h3>Background and aims</h3><div>While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity.</div></div><div><h3>Methods</h3><div>A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators.</div></div><div><h3>Results</h3><div>Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [−4.81, −2.29]), fat mass (MD -2.95 kg, 95 %-CI [−4.11, −1.79]), and lean mass (MD -0.86 kg, 95 %-CI [−1.30, −0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass.</div></div><div><h3>Conclusions</h3><div>Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156113"},"PeriodicalIF":10.8,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1016/j.metabol.2024.156110
Xinliu Zeng , Yongjie Wang , Karina Farias , Andrew Rappa , Christine Darko , Anthony Sauve , Qingxia Huang , Laura C. Alonso , Yue Yang
Aims
NAD+ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD+ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD+ synthesis.
Methods
Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD+ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.
Results
NRH entered tissues unassisted and was rapidly metabolized for NAD+ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD+ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.
Conclusion
This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD+ enhancement.
{"title":"NRH, a potent NAD+ enhancer, improves glucose homeostasis and lipid metabolism in diet-induced obese mice through an active adenosine kinase pathway","authors":"Xinliu Zeng , Yongjie Wang , Karina Farias , Andrew Rappa , Christine Darko , Anthony Sauve , Qingxia Huang , Laura C. Alonso , Yue Yang","doi":"10.1016/j.metabol.2024.156110","DOIUrl":"10.1016/j.metabol.2024.156110","url":null,"abstract":"<div><h3>Aims</h3><div>NAD<sup>+</sup> deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD<sup>+</sup> enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD<sup>+</sup> synthesis.</div></div><div><h3>Methods</h3><div>Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD<sup>+</sup> levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.</div></div><div><h3>Results</h3><div>NRH entered tissues unassisted and was rapidly metabolized for NAD<sup>+</sup> biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD<sup>+</sup> levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.</div></div><div><h3>Conclusion</h3><div>This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD<sup>+</sup> enhancement.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156110"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1016/j.metabol.2024.156111
Xu Zhang , Tianxing Chen , Zhenhan Li , Lingfeng Wan , Zhihang Zhou , Ying Xu , Dong Yan , Wei Zhao , Hao Chen
Background & aims
Abnormal regulation of lncRNA is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (Rock2) axis and the NORAD/ROCK2 interaction in the development of MASLD.
Methods
In vitro and in vivo models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis.
Results
NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate Rock2 mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/Rock2 axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis.
Conclusions
The NORAD/miR-511-3p/Rock2 axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.
{"title":"NORAD exacerbates metabolic dysfunction-associated steatotic liver disease development via the miR-511-3p/Rock2 axis and inhibits ubiquitin-mediated degradation of ROCK2","authors":"Xu Zhang , Tianxing Chen , Zhenhan Li , Lingfeng Wan , Zhihang Zhou , Ying Xu , Dong Yan , Wei Zhao , Hao Chen","doi":"10.1016/j.metabol.2024.156111","DOIUrl":"10.1016/j.metabol.2024.156111","url":null,"abstract":"<div><h3>Background & aims</h3><div>Abnormal regulation of lncRNA is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (<em>Rock2</em>) axis and the NORAD/ROCK2 interaction in the development of MASLD.</div></div><div><h3>Methods</h3><div><em>In vitro</em> and <em>in vivo</em> models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis.</div></div><div><h3>Results</h3><div>NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate <em>Rock2</em> mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/<em>Rock2</em> axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis.</div></div><div><h3>Conclusions</h3><div>The NORAD/miR-511-3p/<em>Rock2</em> axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156111"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1016/j.metabol.2024.156112
Chun Dou , Dong Liu , Lijie Kong, Mingling Chen, Chaojie Ye, Zheng Zhu, Jie Zheng, Min Xu, Yu Xu, Mian Li, Zhiyun Zhao, Jieli Lu, Yuhong Chen, Guang Ning, Weiqing Wang, Yufang Bi, Tiange Wang
Background
Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions.
Methods
In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index.
Results
We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (ABO, AOC1, FTO, GCKR, MTOR, POLK, PPARG, and APEH), with MTOR and PPARG categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles.
Conclusions
Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.
{"title":"Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets","authors":"Chun Dou , Dong Liu , Lijie Kong, Mingling Chen, Chaojie Ye, Zheng Zhu, Jie Zheng, Min Xu, Yu Xu, Mian Li, Zhiyun Zhao, Jieli Lu, Yuhong Chen, Guang Ning, Weiqing Wang, Yufang Bi, Tiange Wang","doi":"10.1016/j.metabol.2024.156112","DOIUrl":"10.1016/j.metabol.2024.156112","url":null,"abstract":"<div><h3>Background</h3><div>Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions.</div></div><div><h3>Methods</h3><div>In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index.</div></div><div><h3>Results</h3><div>We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (<em>ABO</em>, <em>AOC1</em>, <em>FTO</em>, <em>GCKR</em>, <em>MTOR</em>, <em>POLK</em>, <em>PPARG</em>, and <em>APEH</em>), with <em>MTOR</em> and <em>PPARG</em> categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles.</div></div><div><h3>Conclusions</h3><div>Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156112"},"PeriodicalIF":10.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1016/j.metabol.2024.156109
Mei Yang , Jiajie Wang , Zhongyue Liu , Zhihong Li
Skeletal muscle is a crucial tissue for physical activity and energy metabolism. Muscle atrophy, characterized by the loss of muscle mass and strength, contributes to adverse outcomes among individuals. This study elucidated the involvement of the nuclear lamina component PRR14 in transmitting mechanical signals and mediating the impact of exercise on skeletal muscle. The expression of PRR14 demonstrated a positive correlation with exercise, while a decline in adult skeletal muscle is evident in disuse muscle conditions. Genetically, multiple single nucleotide polymorphisms (SNPs) within PRR14's genomic locus were linked with muscle mass and function. Specific knockout (KO) of skeletal muscle Prr14 in mice lead to muscle atrophy, validating the genetic association. By employing biochemical analysis and high-throughput sequencing techniques, including transcriptome profile and epigenome investigations such as Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and Transposase-Accessible Chromatin sequencing (ATAC-seq), we discovered that PRR14's deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, ultimately causing muscle atrophy. Our finding highlights the crucial role of PRR14 in mechanotransduction and epigenetic regulation, offering new therapeutic avenues for skeletal muscle pathologies related to these mechanisms.
{"title":"PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle","authors":"Mei Yang , Jiajie Wang , Zhongyue Liu , Zhihong Li","doi":"10.1016/j.metabol.2024.156109","DOIUrl":"10.1016/j.metabol.2024.156109","url":null,"abstract":"<div><div>Skeletal muscle is a crucial tissue for physical activity and energy metabolism. Muscle atrophy, characterized by the loss of muscle mass and strength, contributes to adverse outcomes among individuals. This study elucidated the involvement of the nuclear lamina component PRR14 in transmitting mechanical signals and mediating the impact of exercise on skeletal muscle. The expression of PRR14 demonstrated a positive correlation with exercise, while a decline in adult skeletal muscle is evident in disuse muscle conditions. Genetically, multiple single nucleotide polymorphisms (SNPs) within PRR14's genomic locus were linked with muscle mass and function. Specific knockout (KO) of skeletal muscle Prr14 in mice lead to muscle atrophy, validating the genetic association. By employing biochemical analysis and high-throughput sequencing techniques, including transcriptome profile and epigenome investigations such as Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and Transposase-Accessible Chromatin sequencing (ATAC-seq), we discovered that PRR14's deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, ultimately causing muscle atrophy. Our finding highlights the crucial role of PRR14 in mechanotransduction and epigenetic regulation, offering new therapeutic avenues for skeletal muscle pathologies related to these mechanisms.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156109"},"PeriodicalIF":10.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-15DOI: 10.1016/j.metabol.2024.156108
Jun-Sik Kim , Jae Hyun Jun , Jeongmi Lee , Sunyoung Park , Eunae Kim , Su Jung Hwang , Heesu Moon , Seung Hyun Baek , Hark Kyun Kim , Jinsu Park , Yoonsuk Cho , Jihoon Han , Chanhee Kim , Jongho Kim , Hyun-Mo Yang , Changsik Lee , Yeonseok Chung , Hyo-Jong Lee , Dong-Gyu Jo
Background
Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration.
Methods
This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet. The therapeutic potential was evaluated from a metabolic perspective, including ocular pathologies such as retinal lesions, neovascularization, and vascular leakage.
Results
We discovered that inhibition or genetic ablation of HDAC6 markedly alleviates DR symptoms by dampening NLRP3 inflammasome activation and mitigating retinal damage. Moreover, bone marrow transplantation from HDAC6-deficient mice into wild-type counterparts reversed DR symptoms, underscoring the significance of HDAC6 in systemic immune regulation. The study introduces a novel HDAC6 inhibitor, noted for superior bioavailability and blood-retinal barrier permeability, further highlights the therapeutic promise of targeting HDAC6 in DR.
Conclusions
Our findings not only underscore the crucial role of HDAC6 in the immune regulatory mechanisms underlying DR pathogenesis through NLRP3 inflammasome activation but also position HDAC6 inhibition as a promising strategy for addressing diabetic complications beyond DR.
{"title":"HDAC6 mediates NLRP3 inflammasome activation in the pathogenesis of diabetic retinopathy","authors":"Jun-Sik Kim , Jae Hyun Jun , Jeongmi Lee , Sunyoung Park , Eunae Kim , Su Jung Hwang , Heesu Moon , Seung Hyun Baek , Hark Kyun Kim , Jinsu Park , Yoonsuk Cho , Jihoon Han , Chanhee Kim , Jongho Kim , Hyun-Mo Yang , Changsik Lee , Yeonseok Chung , Hyo-Jong Lee , Dong-Gyu Jo","doi":"10.1016/j.metabol.2024.156108","DOIUrl":"10.1016/j.metabol.2024.156108","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration.</div></div><div><h3>Methods</h3><div>This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet. The therapeutic potential was evaluated from a metabolic perspective, including ocular pathologies such as retinal lesions, neovascularization, and vascular leakage.</div></div><div><h3>Results</h3><div>We discovered that inhibition or genetic ablation of HDAC6 markedly alleviates DR symptoms by dampening NLRP3 inflammasome activation and mitigating retinal damage. Moreover, bone marrow transplantation from HDAC6-deficient mice into wild-type counterparts reversed DR symptoms, underscoring the significance of HDAC6 in systemic immune regulation. The study introduces a novel HDAC6 inhibitor, noted for superior bioavailability and blood-retinal barrier permeability, further highlights the therapeutic promise of targeting HDAC6 in DR.</div></div><div><h3>Conclusions</h3><div>Our findings not only underscore the crucial role of HDAC6 in the immune regulatory mechanisms underlying DR pathogenesis through NLRP3 inflammasome activation but also position HDAC6 inhibition as a promising strategy for addressing diabetic complications beyond DR.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156108"},"PeriodicalIF":10.8,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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