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Abstract: TH-PO620

Impact of the Gene Encoding Canonical Transient Receptor Potential 1 Channel (TRPC1) on Glucose Intolerance and Liver Steatosis Is Condition-Specific: Role of Hyperphagia, Obesity, and High Fat Diet (HFD)

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Eby, Bonnie, University of Oklahoma Heath Sciences 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 Heath Sciences Center, Oklahoma City, Oklahoma, United States
  • Atkins, Richard Matthew, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States
  • Skaggs, Chris, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Khan, Usman A., University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States
  • Tsiokas, Leonidas, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
Background

We recently noted spontaneous development of metabolic syndrome (MetS) in TRPC1 null mice vs wild type (wt). We now studied the impact of gene dosage, role of adipokines, & responses to a HFD (45%) vs. normal (N) (10-13%) FD x 4 m.

Methods

We did metabolic studies in ♂ littermates of all 3 genotypes, using standard chemical techniques & ELISA for insulin, leptin, & adiponectin

Results

On normal chow, from 4th-5th to 30th week, null mice ate & weighed more than +/- & wt. After 30 weeks, intake & weight gains in null became similar to +/- & wt. At 2 m, null mice had hyperglycemia & hypercholesterolemia. Their livers were 36% heavier & triglyceride content (TGC) 47% higher. Liver echogenicity was elevated by 50-150 % at 7, 11, & 22 m, corroborated by 140% higher liver TGC. At 12 m, only null mice had hyperlipidemia (30% higher blood total cholesterol, 60% higher LDL, & 200% higher TG). In +/- & wt, blood lipids, liver density at 12 & 19 m, & liver TGC at 19 m were all normal. Fasting glucose was elevated only in null (up 20% at 1 m, 23% at 3.5 m & 13% at 15.5 m). Thus on a normal diet, 1 TRPC1 gene allele could prevent hyperphagia, obesity, MetS & hepatic steatosis. As expected, HFD vs. NFD stimulated leptin & insulin, comparably in all 3 genotypes, without affecting adiponectin or weight gains. Contrary to a normal diet, HFD increased liver density in +/- & wt, but unexpectedly & inexplicably, not in null. On NFD, HOMA-IR was similar among all 3 genotypes, but HFD induced the highest HOMA-IR in wt (3.1 vs 1.3 in +/-) & the largest liver TGC hike in wt (3.3 x vs 2 x in +/- vs 1.6 x in null). During glucose tolerance test, the area under the curve for plasma glucose vs time was again paradoxically the highest in wt vs null.

Conclusion

We conclude: 1. Normally, TRPC1 helps maintain glucose & lipid homeostasis, presumably by preventing hyperphagia & obesity seen in diploid deficiency, which renders hypothalamic neurons relatively resistant to anorexigenic effects of lepin. 2. When stressed by a HFD, the wt TRPC1 gene dose-dependently predisposes the mice to glucose intolerance & steatosis. 3. Mechanisms for these diverse effects are unknown but unrelated to changes in insulin, leptin or adiponectin.

Funding

  • NIDDK Support