Central Nervous System Imprinting of the G Protein Gsα and Its Role in Metabolic Regulation

Abstract

Summary Albright hereditary osteodystrophy is a monogenic obesity disorder due to heterozygous mutations of Gsα, the G protein which mediates receptor-stimulated cAMP generation, in which obesity only develops when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline Gsα mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to Gsα imprinting with preferential expression from the maternal allele in some tissues. As Gsα is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific Gsα knockout mice we show that Gsα imprinting within the central nervous system underlies these effects and that Gsα is imprinted in the paraventricular nucleus of the hypothalamus. Maternal Gsα mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both Gsα-dependent and -independent pathways.

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…Animal studies have shown that brain-specific maternal Gsα mutation leads to obesity, severe insulin resistance, and diabetes (Chen et al 2009b). Especially, these mice developed insulin-resistant diabetes before the development of obesity, indicating that central Gsα signaling directly regulates peripheral glucose metabolism.…”

An Essential Role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in Melanocortin-4-receptor-dependent Satiety

“…However, a causative role for cAMP in MC4R signaling that leads to satiety has not to our knowledge been demonstrated. Indeed, loss of G␣ s function in PVN does not influence feeding behavior (23,24). Thus, the mechanism that links MC4R signaling to changes in neuronal firing, and particularly to the control of feeding behavior, remains unknown.…”

Imprinted genes and hypothalamic function

“…PHP1a patients also develop obesity (Long et al 2007) but, since GNAS expression is not imprinted in adult adipose tissue (Mantovani et al 2004, Chen et al 2010, Gsa function in adipocytes is not a major contributor to this metabolic phenotype, despite the key role of Gsa in regulating lipid mobilisation. Instead, evidence from tissue-specific ablation of Gnas in mouse implicates imprinted expression in the hypothalamus as the cause (Chen et al 2009). …”