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 α, δ, γ) 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 PPARα and/or PPARγ may contribute to
weight gain and
obesity. PPARδ 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 PPARδ increases
lipid oxidative genes and opposes
inflammation, we hypothesized that CNS PPARδ 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 PPARδ. 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 PPARγ and target genes of both PPARα and PPARγ, as well as genes of
fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.