Improved Insulin Sensitivity and Resistance to Weight Gain in Mice Null for the Ahsg Gene

Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan, United States
Diabetes (Impact Factor: 8.1). 08/2002; 51(8):2450-8. DOI: 10.2337/diabetes.51.8.2450
Source: PubMed


Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.

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    • "Fetuin-A per se is an endogenous inhibitor of the insulin receptor tyrosine kinase in the liver and skeletal muscle [2], and is crucial in lipid-induced insulin resistance [3]. In animals, fetuin-A knockout mice showed improved insulin signaling, less adiposity, and lower free fatty acid, and were resistant to weight gain upon a high-fat diet compared with wild-type controls [4]. In human studies, fetuin-A is associated with various metabolic dysregulations. "
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    ABSTRACT: Arterial stiffness is a functional assessment of vascular damage caused by cardiovascular disease (CVD) risk factors. Fetuin-A is associated with subclinical CVD and incident or fatal CVD, with some modification of its effect occurring with the presence of diabetes. We investigated the impact of different glycemic statuses and serum fetuin-A levels on arterial stiffness. A total of 312 age- and sex-matched subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed diabetes (NDD) were recruited. Serum fetuin-A levels were measured, and arterial stiffness was assessed by brachial-ankle pulse-wave velocity (baPWV). We found that the mean values of baPWV were 1533±338, 1518±353, 1589±307, 1690±414cm/sec, and fetuin-A levels were 298±69, 313±67, 330±86, 342±93μg/ml, in subjects with NGT, IFG, IGT, and NDD, respectively (both p<0.001, test for trend). NDD subjects had significantly higher baPWV and fetuin-A levels than those with NGT. Multiple linear regression analysis showed that age, fetuin-A, diabetes, hypertension, and hypertriglyceridemia are independently associated factors of baPWV after adjusting for cardiometabolic risk factors, HOMA-IR, and adiponectin. Both diabetes and fetuin-A levels are independently associated with arterial stiffness. Fetuin-A may further aggravate increased arterial stiffness in diabetes. Copyright © 2015. Published by Elsevier B.V.
    Clinica chimica acta; international journal of clinical chemistry 04/2015; 445. DOI:10.1016/j.cca.2015.03.030 · 2.82 Impact Factor
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    • "Fetuin-A has been found to inhibit insulin receptor tyrosine kinase activity (TKA) in mice (Mathews et al., 2002) and humans (Srinivas et al., 1996). TKA plays an essential role in insulin signaling and may help to explain why fetuin-A knockout mice show enhanced glucose sensitivity and clearance, resistance to weight gain (on a high fat diet), decreased serum free-fatty acid levels and decreased body fat compared to controlled mice (on the same high fat diet) (Mathews et al., 2002). Due to this finding, it has been suggested that fetuin-A might be a novel therapeutic target for the treatment of T2DM, obesity and other insulin-resistant conditions. "
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    ABSTRACT: The purpose of this review is to summarize the role of fetuin-A in disease processes prevalent in postmenopausal women and synthesize effective interventions in obtaining healthy fetuin-A levels. A review of databases for articles related to fetuin-A and diseases associated with postmenopausal women was conducted. Articles were limited to full-text access, published in English since 1944. High fetuin-A levels are closely associated with decreased bone mineral density, increased cardiovascular disease risks, impairment of insulin signaling and disruption of adipocyte functioning. Postmenopausal women have increased risk of osteoporosis, cardiovascular disease, insulin-resistance, intra-abdominal fat accumulation and vascular calcification. Low-levels of fetuin-A have been shown to be protective against the latter. The role of fetuin-A is multi-factorial and the mechanisms in which it is involved in each of these processes are vast. The present body of literature is inconsistent in defining high versus low levels of fetuin-A and their association with healthy-matched controls. The diseases associated with high levels of fetuin-A mimic diseases most prevalent in postmenopausal women. In addition, there is no research, to date, exploring fetuin-A levels in postmenopausal women and the associations it may or may not have in related diseases.
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    • "Állatkísérletekben észlelték, hogy az elhízás hatására fokozódik a fetuin-A expressziója [17], és hiányában a testsúlygyarapodás mérséklődik [18]. Humán vizsgálatokban azt tapasztalták, hogy a magasabb fetuin-A-értékhez gyakrabban társult visceralis obesitas [19], illetve a szintje a BMI-vel korrelált [20] "
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    ABSTRACT: Fetuin-A (also known as α2-Heremans-Schmid glycoprotein) is a multifunctional molecule secreted by the liver. It is a negative acute phase reactant with a debated role in subclinical inflammation. Fetuin-A is an inhibitor of the insulin receptor and its serum level correlates with insulin resistance. The protein has been implicated in adipocyte dysfunction and it is associated with obesity and non-alcoholic fatty liver disease. Although all these properties seem to promote atherosclerosis, the role of fetuin-A in cardiovascular diseases is more complex. As a natural inhibitor of tissue and vascular calcification, fetuin-A also acts as a protective factor in atherosclerosis. The potential role and prognostic value of fetuin-A in arterial calcification and cardiovascular diseases is discussed in this review, along with explanations for seemingly contradicting results in the literature and possible directions for future research. Orv. Hetil., 2014, 155(1), 16-23.
    Orvosi Hetilap 01/2014; 155(1):16-23. DOI:10.1556/OH.2014.29793
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