Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice.
Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3- to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.
Sainsbury
Amanda
A
Neurobiology Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Schwarzer
Christoph
C
Couzens
Michelle
M
Fetissov
Serguei
S
Furtinger
Sabine
S
Jenkins
Arthur
A
Cox
Helen M
HM
Sperk
Günther
G
Hökfelt
Tomas
T
Herzog
Herbert
H
D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D005247:Feeding Behavior; D017353:Gene Deletion; D005854:Germ Cells; D007031:Hypothalamus / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D010191:Pancreatic Polypeptide / Q000097:blood; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D010191:Pancreatic Polypeptide; D003345:Corticosterone