1. Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
- Author
-
David Powell, Jason Gay, Melinda Smith, Nathaniel Wilganowski, Angela Harris, Autumn Holland, Maricela Reyes, Laura Kirkham, Laura Kirkpatrick, Brian Zambrowicz, Gwenn Hansen, Kenneth Platt, Isaac van Sligtenhorst, Zhi-Ming Ding, and Urvi Desai
- Subjects
0301 basic medicine ,obesity ,medicine.medical_specialty ,FADS1 ,FADS2 ,medicine.medical_treatment ,delta-6 desaturase ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,Diabetes mellitus ,delta-5 desaturase ,Internal Medicine ,medicine ,Fatty Acid Desaturase 1 ,Targets and Therapy [Diabetes, Metabolic Syndrome and Obesity] ,Original Research ,Pharmacology ,chemistry.chemical_classification ,diabetes ,Triglyceride ,Insulin ,medicine.disease ,Delta-6-desaturase ,030104 developmental biology ,Endocrinology ,chemistry ,atherosclerosis ,Polyunsaturated fatty acid - Abstract
David R Powell,Jason P Gay,Melinda Smith,Nathaniel Wilganowski,Angela Harris,Autumn Holland,Maricela Reyes,Laura Kirkham,Laura L Kirkpatrick,Brian Zambrowicz,Gwenn Hansen,Kenneth A Platt,Isaac van Sligtenhorst,Zhi-Ming Ding,Urvi Desai Metabolism Research, Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA Abstract: Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for w3, w6, and w9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test. In confirmatory studies, chow- or high-fat-diet-fed Fads1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 38% and 31% lower in Fads1 male and female KO mice, respectively. Fads1 KO mice also had lower glucose and insulin excursions during oral glucose tolerance tests along with lower fasting glucose, insulin, triglyceride, and total cholesterol levels. In additional studies using a vascular injury model, Fads1 KO mice had significantly decreased femoral artery intima/media ratios consistent with a decreased inflammatory response in their arterial wall. Based on this result, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a Western diet for 14weeks; in this atherogenic environment, aortic trees of Fads1 KO mice had 40% less atheromatous plaque compared to WT littermates. Importantly, PUFA levels measured in brain and liver phospholipid fractions of Fads1 KO mice were consistent with decreased D5D activity and normal D6D activity. The beneficial metabolic phenotype demonstrated in Fads1 KO mice suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes, and atherosclerotic cardiovascular disease. Keywords: delta-5 desaturase, delta-6 desaturase, obesity, diabetes, atherosclerosis
- Published
- 2016