BBB seminar: Gunnar Mellgren
Homeoproteins in adipose tissue and obesity
Department of Clinical Science, University of Bergen
The continuing increase in the number of obese subjects represents one of the greatest health challenges world-wide (www.who.int). Obesity is strongly correlated with insulin resistance and type 2 diabetes and may lead to debilitating conditions such as heart disease and cancer. Obesity results from excess energy storage relative to expenditure through an interplay between environmental and genetic factors. Heritability explains 40-80 % of individual variability in body weight and genome-wide association studies (GWAS) have pointed to several obesity-linked single-nucleotide variants. Among these, the FTO locus has the strongest known GWAS association with body-mass index in humans. We recently reported that a causal cis-regulatory variant in intron 1 of the FTO gene, rs1421085, affects a molecular switch that controls the bioenergetic fate of individual adipocytes in a cell-autonomous manner. A risk allele-dependent increase in expression of two developmental homeoproteins, IRX3 and IRX5, promoted fat storage by inhibiting adipocyte browning and inducible thermogenesis. Previously, we reported differential expression of these and other homeoproteins in adipose tissue after profound fat loss in morbidly obese bariatric patients. However, causal effects on fat storage remain to be shown in vivo, and discovery of downstream mediators may open new therapeutic avenues. Results from recent studies on Irx5 knockout (KO) mice will be presented pointing to a gene network centered on amyloid precursor protein (APP) that affects mitochondrial respiration in adipocytes.
Chairperson: Johan Fernø, Department of Clinical Science