Neuronal Inactivation of Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions

Abstract

Peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1␣ have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC-1␣ in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1␣ knock-out mice (B␣KO) using calcium/calmodulin-dependent protein kinase II␣ (CaMKII␣)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1␣ null mice, B␣KO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, B␣KO mice are hypermetabolic, and similar to whole body PGC-1␣ null mice, are also resistant to dietinduced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1␣ leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1␣ null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1␣ in the control of energy balance. Our results also implicate CaMKII␣-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo.

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

“…It has been recently shown that genetic ablation of PGC-1␣ leads to impaired induction of orexigenic peptides, such as agouti-related protein (AgRP) and neuropeptide Y (NPY), under fasting conditions (Ma et al, 2010). These results are consistent with the idea that PGC-1␣ coordinates the expression of hypothalamic neuropeptides to cope with changes in energy levels in the body (Coppari et al, 2009).…”

“…Accordingly, knock-out of the oxytocin peptide causes increased intake of animals' selected diets (Amico et al, 2005;Kasahara et al, 2007;Miedlar et al, 2007). Similarly, neuronal inactivation of PGC-1␣ leads to increased food intake (Ma et al, 2010).…”

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

“…The finding, however, that some vacuoles were observed closely attached to and partly encompassed by neuronal structures in MAP-2 and SMI-32 stainings suggests that at least a small proportion of vacuoles within the neuropil can be of neuronal origin, and that the mechanisms which lead to excessive intracellular membrane-bound fluid accumulation may affect different cell-types within the CNS, though to different extents. This hypothesis is supported by the report on CNS vacuoles observed also in neuron-specific PGC-1α knockout mice [25].…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…Neuroprotection through PGC-1 was shown in the contexts of oxidative stress and amyotrophic lateral sclerosis whereas neurodegeneration is associated with a loss of PGC-1 in various disorders including Huntington´s and Alzheimer´s disease [85,[130][131][132]. Consistently, global and brain-specific deletion models of PGC-1 exhibit striatal degenerative lesions and increased susceptibility for other neurodegenerative events [80,133].…”