Obesity and diabetes in transgenic mice expressing proSAAS.
ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone convertase 1 in vitro. To explore the function of proSAAS and its derived peptides, transgenic mice were created which express proSAAS using the beta-actin promoter. The body weight of transgenic mice was normal until approximately 10-12 weeks, and then increased 30-50% over wild-type littermates. Adult transgenic mice had a fat mass approximately twice that of wild-type mice, and fasting blood glucose levels were slightly elevated. In the pituitary, the levels of several fully processed peptides in transgenic mice were not reduced compared with wild-type mice, indicating that the proSAAS transgene did not affect prohormone convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS-derived peptides towards prohormone convertase 1 is much greater in the absence of carboxypeptidase E activity, the proSAAS transgene was also expressed in carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat) mice died between 11 and 26 weeks of age, presumably due to greatly elevated blood glucose. The levels of several pituitary peptides were significantly reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase 1 in these mice. Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1.
Wei
Suwen
S
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Feng
Yun
Y
Che
Fa-Yun
FY
Pan
Hui
H
Mzhavia
Nino
N
Devi
Lakshmi A
LA
McKinzie
Audra A
AA
Levin
Nancy
N
Richards
William G
WG
Fricker
Lloyd D
LD
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition; D001923:Brain Chemistry; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000378:metabolism*; D004435:Eating; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010907:Pituitary Hormones / Q000097:blood; D045664:Proprotein Convertase 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
D001786:Blood Glucose; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C112832:Pcsk1n protein, mouse; D010907:Pituitary Hormones; D012333:RNA, Messenger; D043423:Carboxypeptidase H; D045664:Proprotein Convertase 1