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Marcos Divino Ferreira-Junior Laboratory of Endocrine Physiology and Metabolism, Department of Physiological Sciences, Federal University of Goias, Goiânia, Brazil
Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal

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Keilah Valéria Naves Cavalcante Laboratory of Endocrine Physiology and Metabolism, Department of Physiological Sciences, Federal University of Goias, Goiânia, Brazil

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Carlos Henrique Xavier Systems Neurobiology Laboratory, Department of Physiological Sciences, Federal University of Goias, Goiânia, Brazil

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Emerielle Cristine Vanzela Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

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Antonio Carlos Boschero Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

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Paulo Matafome University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal
University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
Clinical and Academic Centre of Coimbra (CACC), Coimbra, Portugal
Polytechnic University of Coimbra, Coimbra Health School, H&T Research Center, Coimbra, Portugal

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Rodrigo Mello Gomes Laboratory of Endocrine Physiology and Metabolism, Department of Physiological Sciences, Federal University of Goias, Goiânia, Brazil
Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

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Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1–14]. For this, two experimental models were used: (i) LEAP2[1–14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1–14] or MK677. Perinatal GHSR modulation by LEAP2[1–14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.

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Jordan S F Chan Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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Tanin Shafaati Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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John R Ussher Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.

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Soo Yeon Jang Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

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Kyung Mook Choi Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

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Osteosarcopenia, which refers to the concomitant presence of osteoporosis and sarcopenia, is expected to increase in the rapidly progressive aging world, with serious clinical implications. However, the pathophysiology of osteosarcopenia has not been fully elucidated, and no optimal treatment specific to osteosarcopenia is available. The RANKL–RANK pathway is widely used as a therapeutic target for osteoporosis. Growing evidence supports the importance of the RANKL–RANK pathway, not only in bone, but also in muscle, and the therapeutic potential of targeting this pathway in muscle diseases has been noted. The muscles and bones closely communicate with each other through various secretory factors called myokines and osteokines. This review covers the roles of the RANKL–RANK pathway in the bone and muscle and their reciprocal interactions. Moreover, we will suggest future directions to move forward for the treatment of osteosarcopenia to prepare for an upcoming aging society.

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Emre Murat Altinkilic Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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Philipp Augsburger Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

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Amit V Pandey Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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Christa E Flück Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of BioMedical Research, University of Bern, Bern, Switzerland

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Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.

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Huanan Zhang School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University, Yantai, China
Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

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John R Speakman Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK
Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China

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Coffee is one of the three most consumed beverages in the world. It is made by first roasting coffee beans, and then grinding and boiling or steeping the roasted beans in water (brewing). The process of roasting and brewing produces a complex mix of bioactive compounds, including methylxanthines (caffeine, theobromine, theophylline), diterpenes, chlorogenic acid, trigonelline, flavonoids, and hydroxycinnamic acid. In the body, these compounds may be metabolized to produce other bioactive compounds. For example, caffeine is primarily (80%) broken down by demethylation to produce paraxanthine. In the post-ingestion period, levels of paraxanthine may be higher than caffeine due to its slower elimination. Hence, while paraxanthine is not found in coffee itself, it has many of the same properties as caffeine and may be a major contributor to its metabolic effects. The impacts of caffeine and paraxanthine on metabolism relate to their impact on adenosine receptors (notably the A2A receptor). It has been known for almost 100 years that intake of coffee stimulates metabolism by between 5% and 20% for at least 3 h. About half of the increase in metabolic rate after drinking coffee is due to caffeine and derivatives, but the source of the other half is unclear. There are large differences in the response to the same amount of coffee in different individuals, which may be related to caffeine clearance rates, effects of other unknown pathways, genetic polymorphism, age, sex, and body composition.

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Xianxian Huang Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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Jing Liu Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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Guangquan Peng Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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Mingyue Lu Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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Zhongbo Zhou School of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, China

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Neng Jiang Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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Zhiming Yan Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China

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The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagon-like peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field.

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Katarzyna Czarzasta Department of Experimental and Clinical Physiology, Laboratory of Center for Preclinical Research, Medical University of Warsaw, Warszawa, Poland

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Luminita H Pojoga Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts, USA

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Over the past decades, research has clearly established the important role of the mineralocorticoid receptor (MR) in both renal and extra-renal tissues. Recently, caveolin-1 (Cav-1) has emerged as a mediator of MR signaling in several tissues, with implications on cardiovascular and metabolic dysfunction. The main structural component of caveolae (plasma membrane invaginations with diverse functions), Cav-1 is a modulator of cardiovascular function, cellular glucose, and lipid homeostasis, via its effects on signal transduction pathways that mediate inflammatory responses and oxidative stress. In this review, we present evidence indicating an overlap between the roles of the MR and Cav-1 in cardiometabolic disease and the relevant signaling pathways involved. Furthermore, we discuss the potential use of Cav-1 as a biomarker and/or target for MR-mediated dysfunction.

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Wenjun Deng Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China

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Mingyu Xu Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China

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Rui Dong Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China

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Yisha Yan Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China

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Quan Jiang Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China

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Irisin is a recently discovered myokine that facilitates the browning of white adipose tissue, increases glucose uptake in skeletal muscle, and influences metabolic processes in the liver. However, its potential effects on amino acid absorption remained largely unexplored. This study aimed to elucidate the role of irisin in modulating amino acid uptake and delineate the underlying molecular mechanisms involved. To this end, juvenile tilapia were administered intraperitoneal irisin injections at 100 ng/g body weight over 8 weeks. Evaluation of various physiological parameters revealed that irisin supplementation significantly improved the specific growth rate and feed conversion efficiency while reducing feed consumption. Muscle tissue analysis revealed that irisin significantly modified the proximate composition by increasing protein content and reducing lipid levels. It also significantly raised the levels of both essential and non-essential amino acids in the muscle. Histological analysis demonstrated that irisin-stimulated muscle growth through hyperplasia rather than hypertrophy, corroborated by upregulated IGF-1 mRNA and downregulated myostatin mRNA expression. Mechanistic studies in cultured tilapia muscle cells elucidated that irisin activated integrin receptors on muscle cells, which subsequently engaged IGF-1/IGF-1R signaling. Downstream of IGF-1R activation, irisin simultaneously stimulates the ERK1/2 and PI3K/mTORC2/Akt pathways. The convergence of these pathways upregulates L-type amino acid transporter 1 expression, thereby augmenting amino acid uptake into muscle cells. In summary, irisin supplementation in tilapia leads to improved muscle growth, predominantly via hyperplasia and augmented amino acid assimilation, governed by intricate cellular signaling pathways. These findings provide valuable aquaculture applications and novel insights into muscle development.

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Yu Wang Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Fan Li Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Xiaoqian Gao Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Huahui Yu Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Zhiyong Du Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Linyi Li Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Yunhui Du Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Chaowei Hu Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Yanwen Qin Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China
The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

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Hypercholesterolemia is an independent risk factor for cardiovascular disease and lowering circulating levels of low-density lipoprotein cholesterol (LDL-C) can prevent and reduce cardiovascular events. MicroRNA-181d (miR-181d) can reduce the levels of triglycerides and cholesterol esters in cells. However, it is not known whether miR-181d-5p can lower levels of circulating LDL-C. Here, we generated two animal models of hypercholesterolemia to analyze the potential relationship between miR-181d-5p and LDL-C. In hypercholesterolemia model mice, adeno-associated virus (AAV)-mediated liver-directed overexpression of miR-181d-5p decreased the serum levels of cholesterol and LDL-C and the levels of cholesterol and triglyceride in the liver compared with control mice. Target Scan 8.0 indicated Proprotein convertase subtilisin/kexin type 9 (PCSK9) to be a possible target gene of miR-181d-5p, which was confirmed by in vitro experiments. miR-181d-5p could directly interact with both the PCSK9 3′-UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, Dil-LDL uptake assays in PCSK9 knockdown Huh7 cells demonstrated that miR-181d-5p promotion of LDL-C absorption was dependent on PCSK9. Collectively, our findings show that miR-181d-5p targets the PCSK9 3′-UTR to inhibit PCSK9 expression and to reduce serum LDL-C. miR-181d-5p is therefore a new therapeutic target for the development of anti-hypercholesterolemia drugs.

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Gencer Sancar German Center for Diabetes Research, Neuherberg, Germany
Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany

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Andreas L Birkenfeld German Center for Diabetes Research, Neuherberg, Germany
Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany

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The root cause of type 2 diabetes (T2D) is insulin resistance (IR), defined by the failure of cells to respond to circulating insulin to maintain lipid and glucose homeostasis. While the causes of whole-body insulin resistance are multifactorial, a major contributing factor is dysregulation of liver and adipose tissue function. Adipose dysfunction, particularly adipose tissue-IR (adipo-IR), plays a crucial role in the development of hepatic insulin resistance and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of T2D. In this review, we will focus on molecular mechanisms of hepatic insulin resistance and its association with adipose tissue function. A deeper understanding of the pathophysiological mechanisms of the transition from a healthy state to insulin resistance, impaired glucose tolerance, and T2D may enable us to prevent and intervene in the progression to T2D.

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