Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1, a novel neuronal protein that regulates energy balance.
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.
Trevaskis
James
J
Metabolic Research Unit, School of Exercise and Nutrition Sciences, Deakin University, Geelong 3217, Victoria, Australia.
Walder
Ken
K
Foletta
Victoria
V
Kerr-Bayles
Lyndal
L
McMillan
Janine
J
Cooper
Adrian
A
Lee
Scott
S
Bolton
Kristy
K
Prior
Matthew
M
Fahey
Richard
R
Whitecross
Kate
K
Morton
Gregory J
GJ
Schwartz
Michael W
MW
Collier
Greg R
GR
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D051380:GRB2 Adaptor Protein; D005849:Gerbillinae; D007031:Hypothalamus / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018909:src Homology Domains / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; D009419:Nerve Tissue Proteins; C498434:Sh3gl2 protein, mouse