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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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Elisa Villalobos University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Allende Miguelez-Crespo University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Ruth A Morgan University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Scotland’s Rural College, The Roslin Institute, Easter Bush Campus, United Kingdom

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Lisa Ivatt University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Mhairi Paul University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Joanna P Simpson University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Natalie Z M Homer University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Dominic Kurian The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Judit Aguilar The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Rachel A Kline The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Thomas M Wishart The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush Campus, Edinburgh, United Kingdom

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Nicholas M Morton University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Centre for Systems Health and Integrated Metabolic Research, Nottingham Trent University, Nottingham, United Kingdom

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Roland H Stimson University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Ruth Andrew University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Brian R Walker University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Mark Nixon University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high-fat-diet (HFD)-induced obesity. In lean male mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient male mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinaemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

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Andrea Lovdel University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Karla J Suchacki University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Fiona Roberts University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Richard J Sulston University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Robert J Wallace Department of Orthopaedics, The University of Edinburgh, Edinburgh, UK

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Benjamin J Thomas University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Rachel M B Bell University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Iris Pruñonosa Cervera University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Gavin J Macpherson Department of Orthopaedic Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK

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Nicholas M Morton University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK
Centre for Systems Health and Integrated Metabolic Research, Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK

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Natalie Z M Homer University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Karen E Chapman University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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William P Cawthorn University/BHF Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK

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Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

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Nawal A Yahya Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Steven R King Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA

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Bo Shi Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Aisha Shaaban Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Nicole E Whitfield Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Chunmei Yan Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China

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Richard J Kordus Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Gail F Whitman-Elia Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Holly A LaVoie Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA

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Cells actively engaged in de novo steroidogenesis rely on an expansive intracellular network to efficiently transport cholesterol. The final link in the transport chain is STARD1, which transfers cholesterol to the enzyme complex that initiates steroidogenesis. However, the regulation of ovarian STARD1 is not fully characterized, and even less is known about the upstream cytosolic cholesterol transporters STARD4 and STARD6. Here, we identified both STARD4 and STARD6 mRNAs in the human ovary but only detected STARD4 protein since the primary STARD6 transcript turned out to be a splice variant. Corpora lutea contained the highest levels of STARD4 and STARD1 mRNA and STARD1 protein, while STARD4 protein was uniformly distributed across ovarian tissues. Cyclic AMP analog (8Br-cAMP) and phorbol ester (PMA) individually increased STARD1 and STARD4 mRNA along with STARD1 protein and its phosphoform in cultured primary human luteinized granulosa cells (hGCs). STARD6 transcripts and STARD4 protein were unresponsive to these stimuli. Combining lower doses of PMA and 8Br-cAMP blunted the 8Br-cAMP stimulation of STARD1 protein. Increasing cholesterol levels by blocking its conversion to steroid with aminoglutethimide or by adding LDL reduced the STARD4 mRNA response to stimuli. Sterol depletion reduced the STARD1 mRNA and protein response to PMA. These data support a possible role for STARD4, but not STARD6, in supplying cholesterol for steroidogenesis in the ovary. We demonstrate for the first time how cAMP, PMA and sterol pathways separately and in combination differentially regulate STARD4, STARD6 and STARD1 mRNA levels, as well as STARD1 and STARD4 protein in human primary ovarian cells.

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Ryan A Lafferty Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK

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Peter R Flatt Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK

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Victor A Gault Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK

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Nigel Irwin Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK

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Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

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Lorena González Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Ma Eugenia Díaz Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Johanna G Miquet Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Ana I Sotelo Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Diego Fernández Cátedra de Bioquímica Humana, Facultad de Medicina (UBA), Buenos Aires, Argentina

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Fernando P Dominici Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Andrzej Bartke Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois, USA

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Daniel Turyn Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Michael Merkhassine Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA
VCA Colonial Animal Hospital, Ithaca, New York, USA

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Reilly W Coch Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA
Weill Cornell College of Medicine, New York, New York, USA

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Carol E Frederick Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA

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Lucinda L Bennett Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA

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Seth A Peng Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA
Fate Therapeutics, San Diego, California, USA

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Benjamin Morse Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA

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Bethany P Cummings Center for Alimentary and Metabolic Science, Department of Surgery, School of Medicine, University of California, Davis, Sacramento, California, USA
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA

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John P Loftus Loftus Laboratory, Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, New York, USA

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Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes in people associated with glucagon infusions have been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigation. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) – low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90–120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagon’s glucose-independent modulation of the canine plasma metabolome and highlight the dog’s relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.

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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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Amanda A Greenwell 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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Christina T Saed 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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Magnus J Stenlund 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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Indiresh A Mangra-Bala 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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Seyed Amirhossein Tabatabaei Dakhili 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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Kunyan Yang 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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Sally R Ferrari 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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Farah Eaton 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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Keshav Gopal 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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Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide’s ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1 CM−/− mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1 CM−/− mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1 CM−/− mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1 CM−/− mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e′/a′ and E/e′ ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1 CM−/− mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.

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