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Publication
Neuron-specific deletion of peroxisome proliferator-activated receptor delta
(PPARd) in mice leads to increased susceptibility to diet-induced obesity.
Authors Kocalis HE, Turney MK, Printz RL, Laryea GN, Muglia LJ, Davies SS, Stanwood GD,
McGuinness OP, Niswender KD
Submitted By Kevin Niswender on 10/25/2012
Status Published
Journal PLoS ONE
Year 2012
Date Published
Volume : Pages 7 : e42981
PubMed Reference 22916190
Abstract Central nervous system (CNS) lipid accumulation, inflammation and resistance to
adipo-regulatory hormones, such as insulin and leptin, are implicated in the
pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated
receptors (PPAR a, d, ?) are nuclear transcription factors that act as
environmental fatty acid sensors and regulate genes involved in lipid metabolism
and inflammation in response to dietary and endogenous fatty acid ligands. All
three PPAR isoforms are expressed in the CNS at different levels. Recent
evidence suggests that activation of CNS PPARa and/or PPAR? may contribute to
weight gain and obesity. PPARd is the most abundant isoform in the CNS and is
enriched in the hypothalamus, a region of the brain involved in energy
homeostasis regulation. Because in peripheral tissues, expression of PPARd
increases lipid oxidative genes and opposes inflammation, we hypothesized that
CNS PPARd protects against the development of DIO. Indeed, genetic neuronal
deletion using Nes-Cre loxP technology led to elevated fat mass and decreased
lean mass on low-fat diet (LFD), accompanied by leptin resistance and
hypothalamic inflammation. Impaired regulation of neuropeptide expression, as
well as uncoupling protein 2, and abnormal responses to a metabolic challenge,
such as fasting, also occur in the absence of neuronal PPARd. Consistent with
our hypothesis, KO mice gain significantly more fat mass on a high-fat diet
(HFD), yet are surprisingly resistant to diet-induced elevations in CNS
inflammation and lipid accumulation. We detected evidence of upregulation of
PPAR? and target genes of both PPARa and PPAR?, as well as genes of fatty acid
oxidation. Thus, our data reveal a previously underappreciated role for neuronal
PPARd in the regulation of body composition, feeding responses, and in the
regulation of hypothalamic gene expression.




Strains
StrainDevelopment StatusCreation MethodOptions
B6.Cg(129S4)-Ppardtm1Rev Tg(Nes-cre)1KlnPhenotyping completeknockout
View
B6.Cg(129S4)-Ppardtm1Rev/+ Tg(Nes-cre)1KlnPhenotyping completenot applicable
View
B6.Cg-Tg(Nes-cre)1Kln/JPhenotyping completetransgenic
View




Genes
SymbolDescription
Ppardperoxisome proliferator activator receptor delta

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