The incidences of obesity and diabetes are approaching epidemic proportions. Our ultimate goal is to delineate the mechanisms by which G proteins control of food intake, energy expenditure, and glucose metabolism, which may lead to development of therapeutic treatments for obesity and diabetes.
Gsα is a ubiquitously expressed G protein α-subunit that mediates receptor-stimulated cAMP generation. Genetic and epigenetic abnormalities in the Gsα gene GNAS underlie several diseases, including McCune-Albright syndrome, endocrine tumors, and pseudohypoparathyroidism (PHP/Albright hereditary osteodystrophy [AHO]). In addition to skeletal and neurocognitive abnormalities, AHO is also a monogenic obesity disorder in which obesity only occurs when the Gsα loss-of-function mutation is on the maternal allele. This is because GNAS is affected by genomic imprinting, an epigenetic phenomenon leading to parental allele-specific differences in gene expression.
Metabolic syndrome (obesity, diabetes, dyslipidemia) is an increasing public health problem. Monogenic obesity syndromes like AHO provide important insights into genes involved in more common forms of obesity and how these genes regulate metabolism. One of the themes of our research is to understand the role of Gsα in regulating energy and glucose metabolism. Consistent with findings in AHO patients, we showed that mice with a heterozygous germline Gsα deletion on the maternal allele develop obesity, insulin-resistant diabetes, and hypertriglyceridemia due to reduced sympathetic nervous system activity (SNA) and energy expenditure, with no primary effect on food intake, while paternal deletions had a minimal effect on metabolism. Our studies on tissue-specific Gsα mouse models indicate that the parent-of-origin metabolic effects of Gsα mutations do not result from Gsα deficiency in liver, muscle, or adipose tissue. In fact, central nervous system (CNS)-specific Gsα deletion on the maternal allele leads to severe obesity associated with low SNA and energy expenditure without hyperphagia, and insulin-resistant diabetes before the onset of obesity.
Melanocortins act in the CNS via Gsα-coupled receptors (MC4R) to promote negative energy balance by inhibiting food intake and stimulating SNA and energy expenditure. MC4R are expressed in many CNS regions including the paraventricular nucleus (PVN) of the hypothalamus, and MC4R mutations are the most common cause of human monogenic obesity. As Gsα mutations do not affect baseline food intake or the ability of melanocortins to inhibit food intake, it is possible that other MC4R-coupled G proteins are responsible for the melanocortin-inhibited food intake. We are presently exploring the G protein pathways mediating the effect of MC4R on food intake.
Further research is needed to determine which brain regions or specific neuronal populations are responsible for the Gsα deficiency-induced metabolic phenotype, and how central melanocortins control energy balance and glucose metabolism via Gsα-dependent and Gsα-independent pathways.