Abstract
The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity. Whole-body deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1β) disrupts mouse circadian locomotor activity and BAT-regulated thermogenesis, in association with altered gene expression at the central level. We examined whether PGC-1β expression in the ARC is required for proper energy balance and locomotor behavior by generating mice lacking the PGC-1β gene specifically in pro-opiomelanocortin (POMC) neurons. POMC neuron-specific deletion of PGC-1β did not impact locomotor behavior, food intake, body composition, energy fuel utilization and metabolic rate in fed, 24-h fasted and 24-h refed conditions. In contrast, in the fed state, deletion of PGC-1β in POMC cells elevated core body temperature during the nighttime period. Importantly, this higher body temperature is not associated with changes in BAT function and gene expression. Conversely, we provide evidence that mice lacking PGC-1β in POMC neurons are more sensitive to the effect of leptin on heat dissipation. Our data indicate that PGC-1β-expressing POMC neurons are part of a circuit controlling body temperature homeostasis and that PGC-1β function in these neurons is involved in the thermoregulatory effect of leptin.
Highlights
The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity
We show that specific loss of PGC-1β in mouse POMC cells significantly elevates core body temperature (BT) at night, in the absence of change in locomotor activity, energy expenditure and BAT thermogenesis
Deletion of PGC-1β was restricted to the hypothalamus as determined by PCR analysis of the recombination event as well as qPCR evaluation of Cre expression in POMCβ-KO mice (Supplementary Figure 1A,B)
Summary
The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity. Whole-body deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1β) disrupts mouse circadian locomotor activity and BAT-regulated thermogenesis, in association with altered gene expression at the central level. Abbreviations AgRP Agouti-related peptide ARC Arcuate nucleus BAT Brown adipose tissue BT Body temperature CRTL Control Cx Cortex HIPP Hippocampus POMC Pro-opiomelanocortin Ppargc1b/PGC1-β Peroxisome proliferator-activated receptor gamma coactivator 1β WAT White adipose tissue. We have likewise demonstrated that specific deletion of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) in AgRP neurons disrupts leptin sensitivity and food intake[16]. Whether PGC-1β expression in the ARC nucleus is essential for the regulation of behavior and energy balance in the mouse remains unknown
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