Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity.

Abstract

Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-λ in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons.

• Authors: Mauricio D Dorfman, Jordan E Krull, Jarrad M Scarlett, Stephan J Guyenet, Mini P Sajan, Vincent Damian, Hong T Nguyen, Michael Leitges, Gregory J Morton, Robert V Farese, Michael W Schwartz, Joshua P Thaler
• Journal: Diabetes (Diabetes) Vol. 66 Issue 4 Pg. 920-934 (04 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28073831 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• Isoenzymes
• Leptin
• Melanocortins
• Pro-Opiomelanocortin
• Phosphatidylinositol 3-Kinases
• PKC-3 protein
• Protein Kinase C
• protein kinase C lambda
• Glucose

Topics

• Animals
• Diet, High-Fat
• Eating (drug effects, genetics)
• Energy Metabolism (drug effects, genetics)
• Glucose (metabolism)
• Glucose Intolerance (genetics, metabolism)
• Hypothalamus (metabolism)
• Insulin Resistance
• Isoenzymes (genetics)
• Leptin (metabolism)
• Male
• Melanocortins (metabolism)
• Mice
• Neurons (metabolism)
• Obesity (genetics, metabolism)
• Paraventricular Hypothalamic Nucleus (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Pro-Opiomelanocortin (drug effects, metabolism)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Rats
• Signal Transduction
• Weight Gain (drug effects, genetics)