Role of human Kallistatin in glucose and energy homeostasis in mice
Objective: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance an...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782400036X |
| _version_ | 1827301523892207616 |
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| author | Leontine Sandforth Sebastian Brachs Julia Reinke Diana Willmes Gencer Sancar Judith Seigner David Juarez-Lopez Arvid Sandforth Jeffrey D. McBride Jian-Xing Ma Sven Haufe Jens Jordan Andreas L. Birkenfeld |
| author_facet | Leontine Sandforth Sebastian Brachs Julia Reinke Diana Willmes Gencer Sancar Judith Seigner David Juarez-Lopez Arvid Sandforth Jeffrey D. McBride Jian-Xing Ma Sven Haufe Jens Jordan Andreas L. Birkenfeld |
| author_sort | Leontine Sandforth |
| collection | DOAJ |
| description | Objective: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. Methods: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial “Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)” was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. Results: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. Conclusions: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance. |
| first_indexed | 2024-04-24T16:25:52Z |
| format | Article |
| id | doaj.art-8029e4df1a684f388440b641e51135c4 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-24T16:25:52Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
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| series | Molecular Metabolism |
| spelling | doaj.art-8029e4df1a684f388440b641e51135c42024-03-31T04:37:19ZengElsevierMolecular Metabolism2212-87782024-04-0182101905Role of human Kallistatin in glucose and energy homeostasis in miceLeontine Sandforth0Sebastian Brachs1Julia Reinke2Diana Willmes3Gencer Sancar4Judith Seigner5David Juarez-Lopez6Arvid Sandforth7Jeffrey D. McBride8Jian-Xing Ma9Sven Haufe10Jens Jordan11Andreas L. Birkenfeld12Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyDepartment of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, GermanyDepartment of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, GermanyDepartment of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, GermanyInternal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyInternal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyInternal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyInternal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, GermanyDepartment of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USADepartment of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston–Salem, NC 27157, USADepartment of Rehabilitation and Sports Medicine, Hannover Medical School (MHH), Hannover, GermanyInstitute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Medical Faculty, University of Cologne, Cologne, GermanyInternal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany; Department of Diabetes, Life Sciences & Medicine, Cardiovascular Medicine & Life Sciences, King's College London, UK; Corresponding author. Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Otfried-Mueller Str. 10, 72076 Tuebingen, Germany.Objective: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. Methods: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial “Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)” was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. Results: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. Conclusions: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.http://www.sciencedirect.com/science/article/pii/S221287782400036XType 2 diabetesDiet-induced insulin resistanceKallistatinSERPIN A4 |
| spellingShingle | Leontine Sandforth Sebastian Brachs Julia Reinke Diana Willmes Gencer Sancar Judith Seigner David Juarez-Lopez Arvid Sandforth Jeffrey D. McBride Jian-Xing Ma Sven Haufe Jens Jordan Andreas L. Birkenfeld Role of human Kallistatin in glucose and energy homeostasis in mice Molecular Metabolism Type 2 diabetes Diet-induced insulin resistance Kallistatin SERPIN A4 |
| title | Role of human Kallistatin in glucose and energy homeostasis in mice |
| title_full | Role of human Kallistatin in glucose and energy homeostasis in mice |
| title_fullStr | Role of human Kallistatin in glucose and energy homeostasis in mice |
| title_full_unstemmed | Role of human Kallistatin in glucose and energy homeostasis in mice |
| title_short | Role of human Kallistatin in glucose and energy homeostasis in mice |
| title_sort | role of human kallistatin in glucose and energy homeostasis in mice |
| topic | Type 2 diabetes Diet-induced insulin resistance Kallistatin SERPIN A4 |
| url | http://www.sciencedirect.com/science/article/pii/S221287782400036X |
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