my old life

I sometimes miss my old life.  Wait, let me be more precise with my words lest I get lost writing all the things I miss.  I sometimes my days in research.  A project of mine from years back that was shared with another group within the company was recently presented at an endocrinology conference.  It felt good for our data to be included as most of my work ended up going into patents rather than publications.  And in the biological sciences world, publications mean more when it comes to hiring time.  A full publication should be following soon.

PP30-2 Fads1 Knockout Mice Are Lean with Improved Glycemic Control and Decreased Development of Atheromatous Plaque

Program: Abstracts - Orals, Poster Previews, and Posters
Session: PP30-Regulation of Body Weight Via Adipose and Brain Poster Preview
Basic

Sunday, April 3, 2016: 11:30 AM-11:45 AM

Room 258 (BCEC)

Poster Board SUN 600

David R Powell^*1, Jason P Gay¹, Melinda Smith¹, Nathaniel Wilganowski¹, Angela Harris¹, Autumn Holland¹, Maricela Reyes¹, Laura Kirkham¹, Laura Kirkpatrick¹, Brian Zambrowicz¹, Gwenn M. Hansen², Kenneth A Platt¹, Isaac van Sligtenhorst¹, Zhi-Ming Ding¹ and Urvi Desai^1
1Lexicon Pharmaceuticals, Inc., The Woodlands, TX, ²Lexicon Pharmaceuticals, The Woodlands, TX

Delta-5-desaturase (D5D) and D6D, encoded by the fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for the omega-3, -6 and -9 polyunsaturated fatty acids (PUFAs).  Although PUFAs appear to play a role in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways, and the potential value of inhibiting this enzyme to treat metabolic disorders, is not clear.  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 by dual energy x-ray absorptiometry, and were among the most glucose tolerant of 2,489 high fat diet (HFD)-fed KO lines analyzed by oral glucose tolerance test (OGTT). In confirmatory studies, we used quantitative magnetic resonance spectroscopy to show that chow- or HFD-fed Fads1 KO mice were significantly 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 (P < 0.001 for each). Fads1 KO mice also had significantly lower glucose (P < 0.01) and insulin (P < 0.001) excursions during OGTTs along with significantly lower fasting glucose (P < 0.05), insulin (P < 0.01), triglyceride (P < 0.05) and total cholesterol (P < 0.001) levels. In additional studies using a vascular injury model, Fads1 KO mice had significant 62% and 57% decreases in femoral artery intima/media ratio after 16 days of exposure to a copper-containing silicone vascular cuff (P < 0.01 for each independent experiment), consistent with a decreased inflammatory response in the arterial wall of Fads1 KO mice. Based on these results, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a western diet to create an atherogenic environment; after 14 weeks we collected the aortic tree of each mouse, stained it with Sudan IV to identify areas of atheromatous plaque, and found that the aortic trees of male and female Fads1 KO mice had 37% and 44% less plaque, respectively, than did those of their WT littermates (P < 0.05 for each). Importantly, 1) analysis of the arachidonic acid/dihomo-gamma-linolenic acid and the gamma-linolenic acid/linoleic acid ratios in brain and liver phospholipid fractions of Fads1 KO mice were consistent with the combination of markedly decreased D5D activity and normal D6D activity, respectively; and 2) our Fads1 KO mice did not appear to have decreased survival even on diets low in arachidonic acid.  We conclude that these Fads1 KO mice exhibited a beneficial metabolic phenotype, and that this beneficial phenotype suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes and atherosclerotic cardiovascular disease.