Obesity: Segal D

Segal D, Anonymous00062. · Centre for Diabetes and Endocrinology, 18 Eton Road, Parktown, Johannesburg 2198. · S Afr Med J. · Pubmed #19563097 No free full text.

Abstract: The Paediatric and Adolescent Endocrine and Diabetes Society of South Africa (PAEDS-SA) recommends, in line with other international groups, that growth hormone (GH) therapy be considered for children and adolescents with significantly short stature and poor growth velocity in the following instances: GH deficiency; Turner syndrome; Prader-Willi syndrome; small-for-gestational-age children with failure of catch-up growth; idiopathic short stature; and chronic renal insufficiency. We have produced treatment guidelines for the use of GH, designed to allow flexibility to determine coverage on a case-by-case basis. We further recommend that when used for growth promotion, GH therapy should be initiated and monitored by, or in consultation with, a paediatric endocrinologist.

Walder K, Segal D, Jowett J, Blangero J, Collier GR. · Metabolic Research Unit, School of Health Sciences, Deakin University, Pigdons Road, Waurn Ponds, VIC 3217, Australia. · Curr Pharm Des. · Pubmed #12769728 No free full text.

Abstract: New treatments are currently required for the common metabolic diseases obesity and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity and type 2 diabetes is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of these diseases is critical to this process, however identification of genes that contribute to the risk of developing these diseases represents a significant challenge as obesity and type 2 diabetes are complex diseases with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new targets for obesity and diabetes. To date, DNA-based approaches using candidate gene and genome-wide linkage analysis have had limited success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees using variance components based linkage analysis show great promise in robustly identifying genomic regions associated with the development of obesity and diabetes. RNA-based technologies such as cDNA microarrays have identified many genes differentially expressed in tissues of healthy and diseased subjects. Using a combined approach, we are endeavouring to focus attention on differentially expressed genes located in chromosomal regions previously linked with obesity and/or diabetes. Using this strategy, we have identified Beacon as a potential new target for obesity and diabetes.

Collier G, Walder K, De Silva A, Tenne-Brown J, Sanigorski A, Segal D, Kantham L, Augert G. · Metabolic Research Unit, School of Health Sciences, Deakin University, Geelong, Australia. · Ann N Y Acad Sci. · Pubmed #12079868 No free full text.

Abstract: DNA-based approaches to the discovery of genes contributing to the development of type 2 diabetes have not been very successful despite substantial investments of time and money. The multiple gene-gene and gene-environment interactions that influence the development of type 2 diabetes mean that DNA approaches are not the ideal tool for defining the etiology of this complex disease. Gene expression-based technologies may prove to be a more rewarding strategy to identify diabetes candidate genes. There are a number of RNA-based technologies available to identify genes that are differentially expressed in various tissues in type 2 diabetes. These include differential display polymerase chain reaction (ddPCR), suppression subtractive hybridization (SSH), and cDNA microarrays. The power of new technologies to detect differential gene expression is ideally suited to studies utilizing appropriate animal models of human disease. We have shown that the gene expression approach, in combination with an excellent animal model such as the Israeli sand rat (Psammomys obesus), can provide novel genes and pathways that may be important in the disease process and provide novel therapeutic approaches. This paper will describe a new gene discovery, beacon, a novel gene linked with energy intake. As the functional characterization of novel genes discovered in our laboratory using this approach continues, it is anticipated that we will soon be able to compile a definitive list of genes that are important in the development of obesity and type 2 diabetes.

Su H, Gunter JH, de Vries M, Connor T, Wanyonyi S, Newell FS, Segal D, Molero JC, Reizes O, Prins JB, Hutley LJ, Walder K, Whitehead JP. · Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia. · Biochem Biophys Res Commun. · Pubmed #19523919 No free full text.

Abstract: We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.

Bolton K, Segal D, McMillan J, Jowett J, Heilbronn L, Abberton K, Zimmet P, Chisholm D, Collier G, Walder K. · Metabolic Research Unit, School of Exercise and Nutrition Sciences, Deakin University, Waurn Ponds, Victoria, Australia. · Int J Obes (Lond). · Pubmed #18414424 No free full text.

Abstract: OBJECTIVE: To characterize the expression of the small leucine-rich glycoprotein decorin in adipose tissue. DESIGN: Real-time PCR was used to measure decorin gene expression in adipose tissue from normal glucose tolerant (NGT), impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Adipose tissue was fractionated to determine which cells were responsible for decorin expression. The location of decorin protein expression in adipose tissue was determined using immunohistochemistry. Real-time PCR was used to measure decorin mRNA levels in human adipose tissue from 16 insulin-sensitive, 16 insulin-resistant and 6 T2D human subjects. Circulating plasma decorin concentrations were measured by enzyme-linked immunosorbent assay in 145 NGT and 141 T2D human individuals from a large-scale epidemiological study in Mauritius. RESULTS: Decorin mRNA was found to be highly expressed in adipose tissue, and decorin gene expression was significantly higher in visceral than that in subcutaneous adipose tissue depots in both P. obesus and human subjects (P=0.002 and P=0.001, respectively). Decorin mRNA was predominantly expressed by stromal/vascular cells of adipose tissue, and decorin protein in adipose tissue was primarily detected adjacent to blood vessels. Circulating plasma decorin levels in humans were elevated by 12% in T2D (P=0.049) compared to NGT subjects. There was a significant independent correlation between plasma decorin levels and waist-to-hip ratio (WHR, P=0.024). In male subjects, plasma decorin levels were significantly correlated with WHR (P=0.006), and fasting and 2-h glucose levels in an oral glucose tolerance test (P=0.027 and P=0.001, respectively). CONCLUSIONS: Decorin expression in adipose tissue was markedly upregulated in the obese state and may therefore play a role in adipose tissue homeostasis or in pathophysiology associated with obesity.

Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K, Segal D. · Metabolic Research Unit, School of Exercise and Nutrition Sciences, Deakin University, Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia. · Endocrinology. · Pubmed #17640997 links to  free full text

Abstract: Soluble protein hormones are key regulators of a number of metabolic processes, including food intake and insulin sensitivity. We have used a signal sequence trap to identify genes that encode secreted or membrane-bound proteins in Psammomys obesus, an animal model of obesity and type 2 diabetes (T2D). Using this signal sequence trap, we identified the chemokine chemerin as being a novel adipokine. Gene expression of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), was significantly higher in adipose tissue of obese and type 2 diabetic P. obesus compared with lean, normoglycemic P. obesus. Fractionation of P. obesus adipose tissue confirmed that chemerin was predominantly expressed in adipocytes, whereas CMKLR1 was expressed in both adipocytes and stromal-vascular cells of adipose tissue. In 3T3-L1 adipocytes, chemerin was markedly induced during differentiation, whereas CMKLR1 was down-regulated during differentiation. Serum chemerin levels were measured by ELISA in human plasma samples from 114 subjects with T2D and 142 normal glucose tolerant controls. Plasma chemerin levels were not significantly different between subjects with T2D and normal controls. However, in normal glucose tolerant subjects, plasma chemerin levels were significantly associated with body mass index, circulating triglycerides, and blood pressure. Here we report, for the first time, that chemerin is an adipokine, and circulating levels of chemerin are associated with several key aspects of metabolic syndrome.