The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

Abstract

The transcriptional coactivator PGC-1␣ is a key regulator of cellular energy expenditure in peripheral tissues. Recent studies report that PGC-1␣-null mice develop late-onset obesity and that the neuronal inactivation of PGC-1␣ causes increased food intake. However, the exact role of PGC-1␣ in the CNS remains unclear. Here we show that PGC-1␣ directly regulates the expression of the hypothalamic neuropeptide oxytocin, a known central regulator of appetite. We developed a unique genetic approach in the zebrafish, allowing us to monitor and manipulate PGC-1␣ activity in oxytocinergic neurons. We found that PGC-1␣ is coexpressed with oxytocin in the zebrafish hypothalamus. Targeted knockdown of the zebrafish PGC-1␣ gene activity caused a marked decrease in oxytocin mRNA levels and inhibited the expression of a transgenic GFP reporter driven by the oxytocin promoter. The effect of PGC-1␣ loss of function on oxytocin gene activity was rescued by tissue-specific re-expression of either PGC-1␣ or oxytocin precursor in zebrafish oxytocinergic neurons. PGC-1␣ activated the oxytocin promoter in a heterologous cell culture system, and overexpression of PGC-1␣ induced ectopic expression of oxytocin in muscles and neurons. Finally, PGC-1␣ forms an in vivo complex with the oxytocin promoter in fed but not fasted animals. These findings demonstrate that PGC-1␣ is both necessary and sufficient for the production of oxytocin, implicating hypothalamic PGC-1␣ in the direct activation of a hypothalamic hormone known to control energy intake.

CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5

“…These enhancements, in both appetite-suppressing and stimulating pathways, balanced the level of food intake in CCR5 −/− and CCL5 −/− mice which explained why food intake and caloric intake were not altered in knockout (KO) mice in both our study (not shown) as well as in previous reports1718. In addition, Fibroblast growth factor 21 (FGF21), Sirtuin 1 (SIRT-1) and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPAGRC1, PGC-1) play important roles in the control of energy balance and glucose metabolism by acting in the brain to increase energy expenditure and to improve insulin sensitivity44454647484950. The energy and insulin signaling regulatory related genes FGF-21 and PGC-1 were significantly reduced in CCR5 −/− and CCL5 −/− mouse hypothalamus as shown by PCR (Fig.…”

The influences of parental diet and vitamin E intake on the embryonic zebrafish transcriptome

“…The system-wide importance of these cofactors explains the developmental defects, and increased mortalities caused by vitamin E deficiency. PGC1A and PGC1B are integral to zebrafish health and development specifically, they are necessary for oxytocin production in the zebrafish brain (Blechman et al, 2011), and their expression is colocalized with many known zebrafish nuclear receptors (Bertrand et al, 2007). Coupled with the inherent advantages and tractability of the vitamin E deficient zebrafish model, this hypothesized mechanism illuminates a plausible role for vitamin E in development.…”

Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

“…ChIP analysis was performed on 6-day-old larvae (pools of 50 larvae per treatment) or adult mouse PVNs (pools of five punches per treatment) as described in Blechman et al (2011). For IP, we used 4 ml of affinity-purified anti-Otp, 1 ml of anti-Pol II, or control Rabbit IgG.…”