HSD17B12 Is Essential for the Metabolic Homeostasis in Adult Mice

Abstract

Hydroxysteroid 17‐beta dehydrogenase (HSD17B) enzymes have an important role in the regulation of sex steroid metabolism by catalyzing the conversion between 17‐keto and 17‐hydroxysteroids. In addition, some HSD17B enzymes are involved in lipid metabolism. Our data together with other previous studies suggest that HSD17B12 is involved in the elongation of very long chain fatty acids (VLCFAs), presumably in producing arachidonic acid. The enzyme presents with universal expression pattern both in human and mouse. Our previous studies have shown that the global knockout of Hsd17b12 gene in mice is embryonic lethal, which is likely due to its pivotal role in the elongation of VLCFAs during development. The aim of the present study was to determine the role of HSD17B12 at adulthood. We, thus, generated conditional Hsd17b12 knockout mice with exon 2 flanked by loxP sites. The gene was globally deleted by crossing the floxed mice with those expressing the tamoxifen‐inducible Cre recombinase in the Rosa26 locus (HSD17B12cKOrosa26 mice) and by providing tamoxifen treatment at the age of eight weeks. Interestingly, inducing the global gene deletion led to 20% reduction in body weight, associated with drastically reduced amount of both white and brown adipose tissue. Our results with indirect calorimetry showed that food intake and water consumption were dramatically reduced (44% and 65%, respectively) in HSD17B12cKOrosa26 mice, although the hypothalamic regulation of feeding behavior was intact. The loss of appetite might be a consequence of general indisposition of the animals, however, no differences in motor activity was observed between KO and control mice. To study whether the strong metabolic phenotype is caused by an altered adipose tissue function, we then generated an inducible, adipocyte‐specific Hsd17b12 KO model (HSD17B12cKOadipoq) by crossbreeding the floxed mice with those expressing the tamoxifen‐inducible Cre recombinase under adiponectin promoter (Adipoq‐cre/ERT2 mice). Surprisingly, the HSD17B12cKOadipoq mice were viable, presented with normal body weight, and were free of any obvious abnormalities. Because of the high hepatic expression of HSD17B12 in both human and mouse, we generated a liver‐specific knockout mouse by crossbreeding the floxed mouse strain with Albumin‐Cre mouse strain. These mice were viable but presented with lipid accumulation in the hepatocytes at a young age (2 months). The results indicate that HSD17B12 is essential for the metabolic homeostasis in adult mice, while the vital role of the enzyme in metabolic regulation is not due to the high HSD17B12 activity in the adipocytes or hepatocytes. Moreover, the hepatocyte‐specific deletion of Hsd17b12 leads to liver steatosis in mice.Support or Funding InformationThis research was funded by Sigrid Jusélius foundation, Academy of Finland and Drug Research Doctoral Program at the University of Turku.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.