V J M Nies1, D Struik1, M G M Wolfs2, S S Rensen3, E Szalowska4, U A Unmehopa5, K Fluiter6, T P van der Meer2, G Hajmousa7, W A Buurman8, J W Greve9, F Rezaee4, R Shiri-Sverdlov10, R J Vonk4, D F Swaab11, B H R Wolffenbuttel2, J W Jonker1, J V van Vliet-Ostaptchouk2,12. 1. Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands. 4. Centre for Medical Biomics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 5. Department of Endocrinology & Metabolism, Academic Medical Center, Amsterdam, The Netherlands. 6. Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands. 7. Cardiovascular Regenerative Medicine, Department Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 8. School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. 9. Department of Surgery, Zuyderland Medical Center Heerlen; Dutch Obesity Clinic South, Heerlen, The Netherlands. 10. Departments of Molecular Genetics, School of Nutrition & Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands. 11. Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. 12. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract
BACKGROUND/ OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/ METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.
BACKGROUND/ OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/ METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in humanobesity.
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