The genetic basis of obesity and type 2 diabetes: lessons from the new zealand obese mouse, a polygenic model of the metabolic syndrome.
ABSTRACT The New Zealand obese (NZO) mouse is a polygenic model of severe obesity and type 2 diabetes-like hyperglycaemia. Outcross experiments with lean strains have led to the identification of numerous susceptibility loci (quantitative trait loci (QTL)) for adiposity and/or hyperglycaemia. Several major QTL were successfully introgressed into lean strains, and two responsible genes, the RabGAP Tbc1d1 and the transcription factor Zfp69, were so far identified by a conventional strategy of positional cloning. Tbc1d1 controls substrate utilization in muscle; SJL mice carry a loss-of-function variant that shifts substrate oxidation from glucose to fat and suppresses adiposity as well as development of diabetes. The zinc finger domain transcription factor Zfp69 appears to regulate triglyceride storage in adipose tissue. Its normal allele Zfp69 causes a redistribution of triglycerides from gonadal stores to liver, and consequently enhances diabetes when introgressed from SJL into NZO, whereas the loss-of-function variant present in NZO and C57BL/6J reduces the prevalence of diabetes. Data from human patients suggest that the orthologs of both genes may play a role in the pathogenesis of the human metabolic syndrome. In addition to Tbc1d1 and Zfp69, variants of Lepr, Pctp, Abcg1, and Nmur2 located in other QTL were identified as potential candidates by sequencing and functional studies. These results indicate that dissection of the genetic basis of obesity and diabetes in mouse models can identify novel regulatory mechanisms that are relevant for the human disease.
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ABSTRACT: Nonlinear interactions between obesity and genetic risk factors are thought to determine susceptibility to type 2 diabetes. We used genetic obesity as a tool to uncover latent differences in diabetes susceptibility between two mouse strains, C57BL/6J (B6) and BTBR. Although both BTBR and B6 lean mice are euglycemic and glucose tolerant, lean BTBR x B6 F1 male mice are profoundly insulin resistant. We hypothesized that the genetic determinants of the insulin resistance syndrome might also predispose genetically obese mice to severe diabetes. Introgressing the ob allele into BTBR revealed large differences in diabetes susceptibility between the strain backgrounds. In a population of F2-ob/ob mice segregating for BTBR and B6 alleles, we observed large variation in pancreatic compensation for the underlying insulin resistance. We also detected two loci that substantially modify diabetes severity, and a third locus that strongly links to fasting plasma insulin levels. Amplification of the genetic signal from these latent diabetes susceptibility alleles in F2-ob/ob mice permitted discovery of an interaction between the two loci that substantially increased the risk of severe type 2 diabetes.Diabetes 12/2000; 49(11):1946-54. · 7.90 Impact Factor
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ABSTRACT: Spontaneous hyperglycemia, hyperinsulinemia and obesity are common features for at least one period of the lifetime in some strains of mice. Both genetic and environmental factors are involved in the pathogenesis of the diabetes-like syndrome, making these strains excellent models for studies in both obesity and diabetes-like states. The metabolic peculiarities can be due to a dominant gene, as for the yellow obese, or a single recessive gene, as in the obese and the diabetes mouse; or they can be of polygenic origin, as for the KK and the NZO mouse. However, the severity of the metabolic disorder is due to the interaction of the mutant genes iwth modifiers in the bat genes themselves. Studies on the pathophysiology and biochemistry of these animals have revealed interstrain differences, different patterns of development of the metabolic disorder, and different degrees of severity of the diabetes-like syndrome. Although the primary causes of the syndrome remain unclear in some strains, an involvement of hypothalamic feeding centers has been implicated.Metabolism 02/1977; 26(1):59-99. · 3.10 Impact Factor
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ABSTRACT: The inheritance of adiposity levels has been investigated in an intercross of the obese, diabetes-prone NZO and the small, lean SM mouse strains. Adiposity index (AI) was defined as the sum of four fat pad weights divided by body weight. DNA pools from fat and lean mice were analyzed with microsatellite variants to screen the genome for quantitative trait loci (QTLs) affecting AI. Ten significant QTLs affecting AI were identified on Chromosome (Chr) 1 (three loci), Chr 2, Chr 5 (two loci), Chr 6 (two loci), Chr 7, and Chr 17. Most of the QTLs appear to be novel. Several QTLs differentially affect specific fat depots. Thus, Chr 2 and Chr 7 QTLs affect gonadal more than inguinal fat, while the converse is true for the Chr 17 QTL. Gender influences the expression of several of the QTLs. For example, effects of the proximal Chr 1 QTL (Obq7) on AI appears to be primarily in males. The proximal AI QTL on Chr 6 (Obq13) maps near the neuropeptide Y (Npy) locus. Sequence analysis of the Npy gene revealed a 1-nucleotide deletion within a highly conserved portion of the 3' untranslated region in strain NZO. However, the deletion is polymorphic among mouse strains. Furthermore, lack of association between this same variant and AI in previously analyzed crosses raises doubt that it is the basis of Obq13. The present cross is the fourth in a series of intercrosses among 10 inbred strains arranged such that each strain is crossed with each adjacent strain within a circle. This design affords multiple opportunities to analyze each segregating QTL.Mammalian Genome 03/2001; 12(2):95-103. · 2.42 Impact Factor