Src Homology 3-Domain Growth Factor Receptor-Bound 2-Like (Endophilin) Interacting Protein 1, a Novel Neuronal Protein that Regulates Energy Balance

Abstract

To identify genes involved in the central regulation of energy balance, we compared hypothalamic mRNA from lean and obese Psammomys obesus, a polygenic model of obesity, using differential display PCR. One mRNA transcript was observed to be elevated in obese, and obese diabetic, P. obesus compared with lean animals and was subsequently found to be increased 4-fold in the hypothalamus of lethal yellow agouti (A(y)/a) mice, a murine model of obesity and diabetes. Intracerebroventricular infusion of antisense oligonucleotide targeted to this transcript selectively suppressed its hypothalamic mRNA levels and resulted in loss of body weight in both P. obesus and Sprague Dawley rats. Reductions in body weight were mediated by profoundly reduced food intake without a concomitant reduction in metabolic rate. Yeast two-hybrid screening, and confirmation in mammalian cells by bioluminescence resonance energy transfer analysis, demonstrated that the protein it encodes interacts with endophilins, mediators of synaptic vesicle recycling and receptor endocytosis in the brain. We therefore named this transcript Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1). SGIP1 encodes a large proline-rich protein that is expressed predominantly in the brain and is highly conserved between species. Together these data suggest that SGIP1 is an important and novel member of the group of neuronal molecules required for the regulation of energy homeostasis.

Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass

“…Further studies demonstrated that SGIP1 has a role in regulating food intake, where targeted reduction of hypothalamic SGIP1 mRNA inhibited food intake and decreased body weight in both P. obesus and Sprague-Dawley rats. 16 As markers of the metabolic syndrome, we measured several diabetes/obesity-related phenotypes, including fasting plasma glucose, waist:hip ratio, BMI and fat mass. We genotyped 47 polymorphic SNPs in SGIP1 selected for the potential to confer a functional effect on the gene.…”

“…Furthermore, depletion of hypothalamic SGIP1 mRNA reduced body weight by inducing an inappropriately high metabolic rate. 16 Whether genetic variation in the SGIP1 gene acts to alter SGIP1 protein expression remains to be seen and is an important question for future experiments.…”

“…[14][15][16][17] This model has been used to identify genes and metabolic pathways that influence the development of metabolic syndrome and have demonstrated associations with these traits in large human cohorts including ubiquitin-like 5 (refs 18,19) and selenoprotein S. 20 SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) was first discovered by differential display PCR analysis of hypothalamus RNA from lean and obese P. obesus and was found to be exclusively expressed in the central nervous system. 16 SGIP1 expression was increased in the hypothalamus of obese P. obesus and the encoded 828 amino-acid protein colocalized with POMC and NPY, two neuropeptides involved in the regulation of energy balance. Targeted reduction of hypothalamic SGIP1 mRNA by infusion of antisense oligonucleotides inhibited food intake and decreased body weight in P. obesus.…”

“…SGIP1 mRNA expression was also elevated in the hypothalamus of Agouti mice, suggesting a role for this gene in the melanocortin signaling pathway. 16 SGIP1 is an endocytic protein that has a functional role in neuronal systems in energy homeostasis by interacting with endophilins. 16,21 The human homolog of SGIP1 is located on chromosome 1p31.3.…”

“…16 SGIP1 is an endocytic protein that has a functional role in neuronal systems in energy homeostasis by interacting with endophilins. 16,21 The human homolog of SGIP1 is located on chromosome 1p31.3. Genetic linkage studies have reported this region is likely to contain genes influencing obesity phenotypes.…”