Identification of genetic loci associated with different responses to high fat diet induced obesity (DIO) in C57BL/6N and C57BL/6J substrains.

Physiological genomics

PubMedID: 24692188

Heiker JT, Kunath A, Kosacka J, Flehmig G, Knigge A, Kern M, Stumvoll M, Kovacs P, Blüher M, Kloting N. Identification of genetic loci associated with different responses to high fat diet induced obesity (DIO) in C57BL/6N and C57BL/6J substrains. Physiol Genomics. 2014;.
We have recently demonstrated that C57BL/6NTac and C57BL/6JRj substrains are significantly different in their response to high fat diet induced obesity (DIO). The C57BL/6JRj substrain seems to be protected from DIO and genetic differences between C57BL/6J and C57BL/6N substrains at 11 SNP loci have been identified. To define genetic variants as well as differences in parameters of glucose homeostasis and insulin sensitivity between C57BL/6NTac and C57BL/6JRj substrains which may explain the different response to DIO, we analysed 208 first backcross (BC1) hybrids of C57BL/6NTac and C57BL/6JRj [(C57BL/6NTacxC57BL/6JRj)F1xC57BL/6NTac] mice. Body weight, epigonadal and subcutaneous fat mass, circulating leptin, as well as parameters of glucose metabolism were measured after 10 weeks of high fat diet (HFD). Genetic profiling of BC1 hybrids were performed using TaqMan SNP genotyping assays. Furthermore, to assess if SNP polymorphisms could affect mRNA level, gene expression analysis was carried out in murine liver and subcutaneous adipose tissue samples. Human subcutaneous adipose tissue was used to verify murine data of SNAP29. We identified four gender-specific variants which are associated with the extent of HFD induced weight gain and fat depot mass. BC1 hybrids carrying the combination of risk or beneficial alleles exhibit the phenotypical extremes of the parental strains. Murine and human SC expression analysis revealed Snap29 as strongest candidate. Our data indicate an important role of these loci in responsiveness to HFD induced obesity and suggest genes of the synaptic vesicle release system such as Snap29 being involved in the regulation of high fat DIO.