Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain

TY - JOUR

T1 - Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain

AU - Scherer, Thomas

AU - Lindtner, Claudia

AU - O'Hare, James

AU - Hackl, Martina

AU - Zielinski, Elizabeth

AU - Freudenthaler, Angelika

AU - Baumgartner-Parzer, Sabina

AU - Tödter, Klaus

AU - Heeren, Joerg

AU - Krššák, Martin

AU - Scheja, Ludger

AU - Fürnsinn, Clemens

AU - Buettner, Christoph

N1 - © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2016/6

Y1 - 2016/6

N2 - Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.

AB - Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.

KW - Journal Article

U2 - 10.2337/db15-1552

DO - 10.2337/db15-1552

M3 - SCORING: Journal article

C2 - 26861781

VL - 65

SP - 1511

EP - 1520

JO - DIABETES

JF - DIABETES

SN - 0012-1797

IS - 6

ER -