Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque

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,&am...

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Autores principales: Powell DR, Gay JP, Smith M, Wilganowski N, Harris A, Holl, A, Reyes M, Kirkham L, Kirkpatrick LL, Zambrowicz B, Hansen G, Platt KA, van Sligtenhorst I, Ding ZM, Desai U
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Publicado: Dove Medical Press 2016
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spelling oai:doaj.org-article:c5f655ae163d4ae7842aaff60615d74f2021-12-02T08:39:15ZFatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque1178-7007https://doaj.org/article/c5f655ae163d4ae7842aaff60615d74f2016-06-01T00:00:00Zhttps://www.dovepress.com/fatty-acid-desaturase-1-knockout-mice-are-lean-with-improved-glycemic--peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007David 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 14 weeks; 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, atherosclerosisPowell DRGay JPSmith MWilganowski NHarris AHollAReyes MKirkham LKirkpatrick LLZambrowicz BHansen GPlatt KAvan Sligtenhorst IDing ZMDesai UDove Medical Pressarticledelta 5 desaturasedelta 6 desaturaseobesitydiabetesatherosclerosisSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol 2016, Iss Issue 1, Pp 185-199 (2016)
institution DOAJ
collection DOAJ
language EN
topic delta 5 desaturase
delta 6 desaturase
obesity
diabetes
atherosclerosis
Specialties of internal medicine
RC581-951
spellingShingle delta 5 desaturase
delta 6 desaturase
obesity
diabetes
atherosclerosis
Specialties of internal medicine
RC581-951
Powell DR
Gay JP
Smith M
Wilganowski N
Harris A
Holl
A
Reyes M
Kirkham L
Kirkpatrick LL
Zambrowicz B
Hansen G
Platt KA
van Sligtenhorst I
Ding ZM
Desai U
Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
description 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 14 weeks; 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
format article
author Powell DR
Gay JP
Smith M
Wilganowski N
Harris A
Holl
A
Reyes M
Kirkham L
Kirkpatrick LL
Zambrowicz B
Hansen G
Platt KA
van Sligtenhorst I
Ding ZM
Desai U
author_facet Powell DR
Gay JP
Smith M
Wilganowski N
Harris A
Holl
A
Reyes M
Kirkham L
Kirkpatrick LL
Zambrowicz B
Hansen G
Platt KA
van Sligtenhorst I
Ding ZM
Desai U
author_sort Powell DR
title Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
title_short Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
title_full Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
title_fullStr Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
title_full_unstemmed Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
title_sort fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque
publisher Dove Medical Press
publishDate 2016
url https://doaj.org/article/c5f655ae163d4ae7842aaff60615d74f
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