Abstract: SA-PO810
Diploid Gene Deletion of Transient Receptor Potential Canonical 1 (TRPC1) Channel Produces Metabolic Syndrome (MetS) but Prevents Further Liver Steatosis and Dyslipidemia Induced by a High-Fat Diet (HFD)
Session Information
- Health Maintenance, Nutrition, Metabolism - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Health Maintenance, Nutrition, and Metabolism
- 1300 Health Maintenance, Nutrition, and Metabolism
Authors
- Mahmood, Muhammad Bilal, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Eby, Bonnie, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Barron, Lindsay J., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lau, Alexander, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Pantalia, Meghan M., Columbia University, New York, New York, United States
- Khan, Usman A., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Skaggs, Chris D., OU Medical Center, Moore, Oklahoma, United States
- Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
Background
There is growing evidence for the role of TRPC1 in regulating glucose & lipid metabolism. Secretion of insulin, leptin & adiponectin is sensitive to cell free Ca. TRPC1 may mediate the effects of leptin in anorexigenic hypothalamic neurons. TRPC1 iwas found low in diabetes & we recently found hyperglycemia in null mice. We tested if TRPC1 deficiency produces MetS & if 45% HFD x 3 mon aggravates it.
Methods
In age-matched TRPC1 +/+. +/-, & -/- mice, we measured glucose & lipids using standard methods & insulin, leptin, & adiponectin by mouse ELISA. We did glucose tolerance test (GTT) by IP glucose (2 mg/kg) after 13 h fast.
Results
From 4-30 week, null mice ate & weighed more than +/- & wt. At 4 mon, HOMA-insulin resistance (IR) was up 60% & HOMA β down 40%. By 12 mon, HOMA-IR was up 8 fold. At 7 mon, by GTT, both TRPC1 +/- & -/- mice were diabetic. In null, adiponectin was down 11% but leptin up 77%. At 2 mon, total cholesterol was 85% hgher in null, their liver 36% heavier, & triglyceride content (TGC) 47% higher. Liver echogenicity was up by 50-150% at 7, 11, & 22 mon, confirmed by 140% higher liver TGC. At 12 mon, only null mice had hyperlipidemia (cholesterol up 30%, LDL up 60%, & TG up 200%). In +/- & wt, lipids, liver density at 12 & 19 mon, & liver TGC at 19 mon were all normal. Fasting glucose was high only in null from 1 through 16 mon). Thus on a normal fat diet (NFD), 1 wt allele prevented hyperphagia, obesity, MetS & hepatic steatosis. As expected, HFD vs NFD stimulated leptin & insulin, similarly in all 3 genotypes without altering adiponectin. Unlike NFD, HFD increased liver density in +/- & wt, but not in null. HFD induced the highest HOMA-IR in wt (3.1 vs 1.3 x in +/-) & the largest liver TGC hike in wt (3.3 vs 1.6 x in null). During GTT, AUC for glucose vs time was the highest in wt vs null.
Conclusion
1. Diploid TRPC1 deletion produces hyperphagia, obesity & Met S, all resolvable by caloric restriction, implying hypothalamic resistance to leptin in null mice. 2. HFD raises the risks of dyslipidemia & hepatic steatosis, only in the presence of 1-2 wt alleles, as if deficiency would block the pathogenic Ca-CM-NFAT signaling pathway. 3. TRPC1 -/- is a good model to study MetS.
Funding
- NIDDK Support