Liver-Derived IGF-I is of Importance for Normal Carbohydrate and Lipid Metabolism

Sjögren, Klara; Wallenius, Kristina; Liu, Jun Li; Bohlooly‐Y, Mohammad; Pacini, Giovanni; Svensson, Lennart; Törnell, Jan; Isaksson, Olle; Åhrén, Bo; Jansson, John‐Olov; Ohlsson, Claes

doi:10.2337/diabetes.50.7.1539

Cited by 125 publications

(102 citation statements)

References 54 publications

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“…This phenotype might be caused by the intrinsic growth retardation of systemic Irs1 -/-deficiency exacerbated by reduced Igf1 signaling. Although overall body growth is not reduced upon deletion of the hepatic Igf1 gene, hepatic Igf1 knockout reduces systemic fat production (68). Moreover, the reduced growth of the Irs1 -/-mice is likely to be exacerbated in the LKO::Irs1 -/-mice by the elevated expression of Igfbp1 (5-fold change compared with control), and the reduced expression of Igfals and Ghr (both reduced 3-fold compared with control) (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Dong¹,

Park²,

Lin³

et al. 2006

J. Clin. Invest.

193

141

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Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs1 from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1 -/-mice (called LKO::Irs1 -/-). Viable LKO::Irs1 -/-mice were 70% smaller than WT or LKO mice, and 40% smaller than Irs1 -/-mice. Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1 -/-and LKO liver, and undetected in LKO::Irs1 -/-liver; however, Gsk3β phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. LKO and Irs1 -/-mice developed insulin resistance and glucose intolerance that never progressed to diabetes, whereas LKO::Irs1 -/-mice developed hyperglycemia and hyperinsulinemia immediately after birth. Regardless, few hepatic genes changed expression significantly in Irs1 -/-or LKO mice, whereas hundreds of genes changed in LKO::Irs1 -/-mice -including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth.

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Section: Discussionmentioning

confidence: 99%

Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Dong¹,

Park²,

Lin³

et al. 2006

J. Clin. Invest.

193

141

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“…A possible mechanism could be IL-1 effects at the level of the hypothalamus (28) that influence the neuroendocrine regulation of growth hormone secretion (40). It cannot be ruled out that the increase in serum IGF-I also contributes to the increased obesity (41) or that the obesity affects the serum IGF-I levels. The increase in fat mass was larger than the increase in LBM, causing a decrease in relative LBM.…”

Section: Discussionmentioning

confidence: 99%

Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice

et al. 2006

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Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI؊/؊ mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5-to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI؊/؊ mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young preobese IL-1RI ؊/؊ mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in preobese IL-1RI ؊/؊ mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity. Diabetes 55: [1205][1206][1207][1208][1209][1210][1211][1212][1213] 2006 T he prevalence of obesity is growing rapidly in many parts of the world and reaching epidemic proportions in several developed countries (1). Overweight and obesity are associated with increased risk of metabolic disorders, such as type 2 diabetes and hyperlipidemia, and thereby increased risk of cardiovascular mortality. Although the regulation of body weight and body composition involves input from lifestyle and environment, compelling scientific evidence indicates that propensity to develop obesity is in large part attributable to genetic factors. Over the last decade, the study of different transgenic and knockout mouse models has contributed to the identification of new factors involved in the complex mechanisms regulating energy balance and to the clarification of the contribution of genetics to obesity (2,3). Moreover, a number of human genes have been identified in which major missense or nonsense mutations as well as genetic variations are associated with obesityrelated phenotypes. Many of these genetic variants have occurred in molecules identical or similar to those identified as a cause of obesity in rodents, supporting their involvement in the regulation of body weight homeostasis also in humans (4).Interleukin-1 (IL-1) is a major mediator of inflammation and exerts effects on the neuro-immuno-endocrine system (5). Infection, injury, and inflammation are associated with negative energy balance, characterized by reduced food intake, weight loss, increased thermogenesis, and fever. IL-1 could be of importance for these effects, as peripheral or central injection of IL-1 induces a marked rise in body temperature (f...

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“…Animals with liver-specific insulin-like growth factor-1 (IGF1) gene deletion are characterized by insulin resistance and hyperinsulinemia (12,13). Low serum IGF1 levels are also associated with determinants of the metabolic syndrome including insulin resistance, serum leptin levels, waist-to-hip ratio, and type 2 diabetes mellitus (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample

Völzke

Nauck²,

Rettig³

et al. 2009

European Journal of Endocrinology

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Context: It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations. Objectives: The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context. Design: We analyzed data from the population-based Study of Health in Pomerania. Methods: We used data from 3863 subjects (1971 women) aged 20-79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays. Results: Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption. Conclusions: Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.

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Liver-Derived IGF-I is of Importance for Normal Carbohydrate and Lipid Metabolism

Cited by 125 publications

References 54 publications

Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice

Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample

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