Alleles on Rat Chromosome 4 (D4Got41‐Fabp1/Tacr1) Regulate Subphenotypes of Obesity

Abstract

KLÖ TING, NORA, BARBARA WILKE, AND INGRID KLÖ TING. Alleles on rat chromosome 4 (D4Got41-Fabp1/ Tacr1) regulate subphenotypes of obesity. Obes Res. 2005; 13:589 -595. Objective: The use of inbred animal models is an essential component of the genetic dissection of complex diseases. Because quantitative trait loci for serum triglycerides, total cholesterol, and body weight were mapped on chromosome 4 in a cross of BioBreeding/OttawaKarlsburg (BB/OK) and spontaneously hypertensive (SHR) rats, we established a congenic BB.SHR rat strain by introgressing a SHR segment of chromosome 4 (D4Got41-Tacr1) into a BB/OK background. The phenotype of these BB.SHR rats (BB.4S) confirmed the quantitative trait loci. To discover whether the phenotype of BB.4S can only be attributed to the SHR segment per se, we established an additional congenic BB.WOKW strain by introgressing a similar segment of chromosome 4 (D4Got41-Fabp1) of the Wistar Ottawa Karlsburg RT1 u rat into a BB/OK background, termed briefly BB.4W. (20), and BB.4W (16) rats were longitudinally studied for body weight, serum triglycerides, total and high-density lipoprotein-cholesterol, and glucose tolerance. At the end of the observation period (32 weeks), serum insulin, leptin, and adiposity index (AI) were determined. Results and Discussion: Congenic BB.4S and BB.4W were significantly heavier, and AI, serum triglycerides, and total cholesterol values were significantly elevated in BB.4S and BB.4W compared with BB/OK but more pronounced in BB.4S. The highest serum insulin was found in BB.4W and highest leptin in BB.4S. Because the body weight gain and AI were comparable between BB.4S and BB.4W, the obviously higher insulin levels in BB.4W and higher leptin values in BB.4S suggest that the two congenics most probably define two subphenotypes of obesity and provide the unique opportunity to study their genetics. Research Methods and Procedures: Male normoglycemic BB/OK (20), BB.4S

Sex dimorphism and depot differences in adipose tissue function

“…Retinol-binding protein 4 (RBP4), a protein released from adipocytes and associated with obesity and insulin resistance, is preferentially produced by VAT and is a marker of intra-abdominal adipose tissue expansion [172]. Plasminogen activator inhibitor 1 (PAI1), an inhibitor of fibrinolysis, is strongly up-regulated in VAT depots, and plasma levels correlate with trunk fat mass in obesity [173], suggesting a plausible link between obesity and thrombotic disorders [174].…”

Gene expression profiling supports the role of Repin1 in the pathophysiology of metabolic syndrome

“…The phenotypic characterization of both congenic strains termed BB.4S (D4Got41-Tracr1; 60.5-122.8 Mb) and BB.4W (D4Got41-Fabp1; 60.5-104.6 Mb) showed that the strains develop obesity, dyslipidemia, hyperleptinemia (BB.4S) or hyperinsulinemia (BB.4W) compared with parental strain BioBreeding/OttawaKarlsburg (BB/OK). In contrast to parental BB/OK rats developing type 1 diabetes at a frequency of more than 86% [7], none of the congenic BB.4S [8], and BB.4W [6] rats developed diabetes. All congenic rats remained normoglycemic up to an age of 30 weeks, which was attributable to the lack of diabetogenic gene Iddm2 (Gimap5), an essential gene for type 1 diabetes development in BB/OK rats.…”

“…In contrast to their parental strain BB/OK, congenic BB.4S and BB.4W do not develop type 1 diabetes, but they manifest facets of metabolic syndrome [6]. Because BB.4S and BB.4W showed comparable facets of metabolic syndrome, it was not surprising that both congenic strains differed in the relative expression of selected genes when compared with their parental BB/OK strain.…”

“…In several crossing studies quantitative trait loci (QTLs) were found for serum triglycerides and total cholesterol mapped on chromosome 4 [4][5][6]. To determine the physiologic relevance of these QTLs, two congenic BB rat strains were established using SHR or WOKW rats as donors of chromosome 4 segment.…”

The Long Way from Complex Phenotypes to Genes: The Story of Rat Chromosome 4 and Its Behavioral Effects

“…In addition, many QTLs not related to neurobiological traits were identified on rat Chr. 4, such as for bone mineral density [57], blood pressure [58] and body weight [59], among others [23]. These findings suggest that Chr.…”