| Autor: |
Geisler, Caroline. E., Ghimire, Susma., Hepler, Chelsea., Higgins, Mark. R., Fregosi, Ralph. F., Renquist, Benjamin. J. |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| DOI: |
10.1101/475608 |
| Popis: |
The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing and diet induced obesity increases hepatic GABA release in mice. Hepatic GABA release decreases hepatic afferent vagal nerve activity to stimulate pancreatic insulin release and decreases insulin sensitivity. Surgically eliminating the hepatic vagal nerve signaling, preventing hepatic GABA synthesis, or limiting hepatic GABA export ameliorates hyperinsulinemia and insulin resistance in diet-induced obese mice. This work establishes that limiting hepatocyte GABA production or release may mute the glucoregulatory dysfunction common to obesity. Competing Interests The results presented in this paper have resulted in patent cooperation treaty Application No. 62/511,753 and 62/647,468: METHODS AND COMPOSITIONS FOR REGULATING GLUCOSE HOMEOSTASIS. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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