Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

Abstract

Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity.

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…The intensity of inflammation is greatly reduced during week 2 and 3, and only to return after 3-4 weeks with much higher intensity (17). Upon persistence of feeding on a high-fat diet (HFD), hypothalamic inflammation is enhanced (thus, characterizing a disturbance in resolution phase) by the activation of additional mechanisms, such as endoplasmic reticulum stress (ERS) and protein kinase-C-theta (PKCϴ (14,16,34), which in the long run will play important roles in the inflammatory-associated damage of the hypothalamus.…”

Control of energy homeostasis by amylin

“…Obesity-related resistance also appears to be partly due to changes in the blood-brain barrier permeability for leptin and insulin [133][134][135][136][137]; interestingly, similar but body weight-independent changes can already be induced by a relatively brief exposure to a high fat diet, i.e. before obesity develops [138][139][140]. Finally, hyperleptinemia which develops as a consequence of reduced sensitivity to leptin in obesity per se seems to reduce further the animals' sensitivity to the action of leptin [141].…”

Ghrelin modulates hypothalamic fatty acid-sensing and control of food intake in rainbow trout

“…These neurons integrate information of peripheral signals, such as i) changes in the levels of nutrients/metabolites like glucose, fatty acids (MCFA) through several mechanisms such as i) fatty acid metabolism by means of inhibition of carnitine palmitoyltransferase 1 (CPT1) to import fatty acid-CoA into the mitochondria for oxidation; ii) binding to fatty acid translocase (FAT/CD36), and further modulation of transcription factors like peroxisome proliferatoractivated receptor type alpha (PPARa), and sterol regulatory element-binding protein type 1c (SREBP1c); iii) activation of protein kinase C-theta; and iv) mitochondrial production of reactive oxygen species (ROS) by electron leakage, resulting in an inhibition of ATP-dependent inward rectifier potassium channel (K ATP ) activity (Ló pez et al 2007, Benoit et al 2009, Blouet & Schwart 2010. The activation of these systems, together with changes in the activity of integrative sensors like 5 0 -AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), is associated with the inhibition of the orexigenic factors AgRP and NPY and the enhancement of the anorexigenic factors POMC and CART, ultimately leading to decreased food intake (Migrenne et al 2007, Blouet & Schwartz 2010.…”