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      ALK7 Gene Polymorphism is Associated with Metabolic Syndrome Risk and Cardiovascular Remodeling

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          Abstract

          Background

          Activin receptor-like kinase 7 (ALK7) is a type I receptor for the TGF-β superfamily and has recently been demonstrated to play an important role in the maintenance of metabolic homeostasis.

          Objective

          To investigate the association of the ALK7 gene polymorphism with metabolic syndrome (MetS) and cardiovascular remodeling in MetS patients.

          Methods

          The single nucleotide polymorphism rs13010956 in the ALK7 gene was genotyped in 351 Chinese subjects undergoing carotid and cardiac ultrasonography. The associations of the ALK7 gene polymorphism with the MetS phenotype, MetS parameters, and cardiovascular ultrasonic features were analyzed.

          Results

          The rs13010956 polymorphism in the ALK7 gene was found to be significantly associated with the MetS phenotype in females (p < 0.05) and was also significantly associated with blood pressure in the total (p < 0.05) and female populations (p < 0.01). Further analysis revealed that rs13010956 was associated with mean intima-media thickness of the carotid arteries in females (p < 0.05). After control for body mass index, blood pressure, fasting blood glucose, and triglycerides, rs13010956 was also found to be significantly associated with left ventricular mass index in the total (p < 0.05) and female populations (p < 0.05).

          Conclusion

          Our findings suggested that the ALK7 gene polymorphism rs13010956 was significantly associated with MetS risk in females and may be involved in cardiovascular remodeling in MetS patients.

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          Most cited references 21

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          Banting lecture 1988. Role of insulin resistance in human disease.

           G M Reaven (1988)
          Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)
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            Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity.

            Growth/differentiation factor 3 (GDF3) is highly expressed in adipose tissue, and previous overexpression experiments in mice have suggested that it may act as an adipogenic factor under conditions of high lipid load. GDF3 has been shown to signal via the activin receptor ALK4 during embryogenesis, but functional receptors in adipose tissue are unknown. In this study, we show that Gdf3(-/-) mutant mice accumulate less adipose tissue than WT animals and show partial resistance to high-fat diet-induced obesity despite similar food intake. We also demonstrate that GDF3 can signal via the ALK4-homolog ALK7 and the coreceptor Cripto, both of which are expressed in adipose tissue. In agreement with a role for ALK7 in GDF3 signaling in vivo, mutant mice lacking ALK7 also showed reduced fat accumulation and partial resistance to diet-induced obesity. We propose that GDF3 regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the ALK7 receptor.
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              Activin isoforms signal through type I receptor serine/threonine kinase ALK7.

              Activins play a fundamental role in cell differentiation and development. Activin A signaling is mediated through a combination of activin type II receptors (ActRIIs) and the activin type IB receptor, ALK4. Signaling receptors of other activin isoforms remain to be elucidated. Here, we found that activin AB and activin B are ligands for ALK7. ALK7 is an orphan receptor serine/threonine kinase expressed in neuroendocrine tissues including pancreatic islets. The combination of ActRIIA and ALK7, preferred by activin AB and activin B but not by activin A, is responsible for activin-mediated secretion of insulin from pancreatic beta cell line, MIN6. In contrast, all activins activate a combination of ActRIIA and ALK4 with various levels of potency. Thus, variation in activin signaling through type I receptors is dependent upon homo- and heterodimeric assembly of activin isoforms. Thus, the differential combination of receptor heterodimers mediates variation in activin isoform signaling.
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                Author and article information

                Journal
                Arq Bras Cardiol
                Arq. Bras. Cardiol
                Arq. Bras. Cardiol.
                Arquivos brasileiros de cardiologia
                Sociedade Brasileira de Cardiologia
                0066-782X
                1678-4170
                August 2013
                : 101
                : 2
                : 134-140
                Affiliations
                [1 ]Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan - China
                [2 ]Department of Emergency, Qilu Hospital of Shandong University, Jinan - China
                [3 ]Department of Geriatrics, Qilu Hospital of Shandong University, Jinan - China
                Author notes
                Mailing Address: Mengxiong Tang, 107#, Wenhua Xi Road, Jinan, Shandong, 250012, China, E-mail: tangmengxiongsdu8@ 123456163.com
                Article
                10.5935/abc.20130129
                3998149
                23765385

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: Independent Innovation Foundation of Shandong University
                Award ID: 2009TS069
                Funded by: Scientific Research Foundation for the Excellent Middle-Aged and Youth Scientists of Shandong Province
                Award ID: BS2011YY013
                Funded by: Key Technologies R & D Program of Shandong Province
                Award ID: 2010G0020262
                Funded by: Natural Science Foundation of Shandong Province
                Award ID: ZR2009CM022
                Award ID: ZR2009CM025
                Award ID: BS2009YY026
                Funded by: Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry
                Funded by: National Natural Science Foundation of China
                Award ID: 81070192
                Award ID: 30971215
                Award ID: 81070141
                Award ID: 81100605
                Categories
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