Impaired mTORC2 signaling in catecholaminergic neurons exaggerates high fat diet-induced hyperphagia

Academic Article

Abstract

  • Objective Food intake is highly regulated by central homeostatic and hedonic mechanisms in response to peripheral and environmental cues. Neutral energy balance stems from proper integration of homeostatic signals with those "sensing" the rewarding properties of food. Impairments in brain insulin signaling causes dysregulation of feeding behaviors and, as a consequence, hyperphagia. Here, we sought to determine how the mammalian target of rapamycin complex 2 (mTORC2), a complex involved in insulin signaling, influences high fat feeding. Methods Rictor is a subunit of mTORC2, and its genetic deletion impairs mTORC2 activity. We used Cre-LoxP technology to delete Rictorin tyrosine hydroxylase (TH) expressing neurons (TH Rictor KO). We assessed food intake, body weight, body composition and DA dependent behaviors. Results TH Rictor KO mice display a high-fat diet specific hyperphagia, yet, when on low-fat diet, their food intake is indistinguishable from controls. Consistently, TH Rictor KO become obese only while consuming high-fat diet. This is paralleled by reduced brain DA content, and disruption of DA dependent behaviors including increased novelty-induced hyperactivity and exaggerated response to the psycho stimulant amphetamine (AMPH). Conclusions Our data support a model in which mTORC2 signaling within catecholaminergic neurons constrains consumption of a high-fat diet, while disruption causes high-fat diet-specific exaggerated hyperphagia. In parallel, impaired mTORC2 signaling leads to aberrant striatal DA neurotransmission, which has been associated with obesity in human and animal models, as well as with escalating substance abuse. These data suggest that defects localized to the catecholaminergic pathways are capable of overriding homeostatic circuits, leading to obesity, metabolic impairment, and aberrant DA-dependent behaviors.
  • Authors

    Published In

  • Heliyon  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 20977258
  • Author List

  • Dadalko OI; Niswender K; Galli A
  • Volume

  • 1
  • Issue

  • 1