Bovine Growth Hormone Transgenic Mice Are Resistant to Diet-Induced Obesity but Develop Hyperphagia, Dyslipidemia, and Diabetes on a High-Fat Diet

Olsson, Bob; Bohlooly‐Y, Mohammad; Fitzgerald, Sharyn M.; Frick, Fredrik; Ljungberg, Anna; Åhrén, Bo; Törnell, Jan; Bergström, Göran; Oscarsson, Jan

doi:10.1210/en.2004-1232

Cited by 73 publications

(74 citation statements)

References 54 publications

(72 reference statements)

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“…In contrast, the gains in lean mass became more prominent with each additional week of treatment. The ability of growth hormone to protect mice from diet-induced fat accumulation and to redirect nutrient partitioning away from adipose tissue and into lean tissue has been reported previously in growth hormone transgenic mice [21,23]. However, both of these studies used mice engineered to have chronically elevated growth hormone levels, representing more of an acromegalic state, and not a daily dosing therapy as performed in this study.…”

Section: Discussionmentioning

confidence: 75%

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

et al. 2009

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Aims/hypothesis Growth hormone has been used experimentally in two studies to treat individuals with type 2 diabetes, with both reporting beneficial effects on glucose metabolism. However, concerns over potential diabetogenic actions of growth hormone complicate its anticipated use to treat type 2 diabetes. Thus, an animal model of type 2 diabetes could help evaluate the effects of growth hormone for treating this condition. Methods Male C57BL/6J mice were placed on a high-fat diet to induce obesity and type 2 diabetes. Starting at 16 weeks of age, mice were treated once daily for 6 weeks with one of four different doses of growth hormone. Body weight, body composition, fasting blood glucose, insulin, glucose tolerance, liver triacylglycerol, tissue weights and blood chemistries were determined. Results Body composition measurements revealed a dosedependent decrease in fat and an increase in lean mass. Analysis of fat loss by depot revealed that subcutaneous and mesenteric fat was the most sensitive to growth hormone treatment. In addition, growth hormone treatment resulted in improvement in glucose metabolism, with the highest dose normalising glucose, glucose tolerance and liver triacylglycerol. In contrast, insulin levels were not altered by the treatment, nor did organ weights change. However, fasting plasma leptin and resistin were significantly decreased after growth hormone treatment. Conclusions/interpretation Growth hormone therapy improves glucose metabolism in this mouse model of obesity and type 2 diabetes, providing a means to explore the molecular mechanism(s) of this treatment.

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Section: Discussionmentioning

confidence: 75%

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

et al. 2009

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“…1B), resulting in relative hypoglycemia. This observation contrasts with the susceptibility of C57BL/6-Tg bGH mice to type 2 diabetes in a high-fat diet study (18). In histological analyses, NOD-Tg bGH mice showed giant islets with anomalous morphology and a periinsular mononuclear cell infiltrate that characterizes the initial stages of diabetes ( Fig.…”

Section: Significancementioning

confidence: 74%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

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“…In transgenic mice, overexpressing IGF1, hypoglycemia, and resistance to diabetes were found (23). However, mice overexpressing GH have high-IGF1, insulin resistance, and increased likelihood of developing diabetes (24).…”

Section: Discussionmentioning

confidence: 99%

Prediction of incident diabetes mellitus by baseline IGF1 levels

Schneider

Friedrich

Klotsche

et al. 2011

European Journal of Endocrinology

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Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low-or high-IGF1 are at risk of diabetes. We hypothesized that both low-and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study. Design: An analysis of two prospective cohort studies, the DETECT study and SHIP. Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up. Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (PO0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age-and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07-1.94) and 1.55 (95% CI 1.06-2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline. Conclusions: Subjects with low-or high-IGF1 level are at increased risk of developing diabetes.

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Bovine Growth Hormone Transgenic Mice Are Resistant to Diet-Induced Obesity but Develop Hyperphagia, Dyslipidemia, and Diabetes on a High-Fat Diet

Cited by 73 publications

References 54 publications

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

Growth hormone prevents the development of autoimmune diabetes

Prediction of incident diabetes mellitus by baseline IGF1 levels

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