Maxadilan and its truncated variant, M65, are agonist and antagonist specific, respectively, for the
PAC1 receptor. PAC1 is the specific receptor for the pituitary
adenylate cyclase-activating
peptide (
PACAP), which is not shared by
vasoactive intestinal peptide (VIP).
PACAP is a ubiquitous
peptide of the
glucagon superfamily that is involved in
glucose homeostasis and regulation of insulin secretion. This study employed the recombinant
maxadilan and M65 to evaluate the
PAC1 receptor-mediated effects on energy metabolism using NIH mice. First, the acute effect of
maxadilan-induced
hyperglycemia was blocked by M65. In long-term studies, NIH mice were given daily
intraperitoneal injections with
maxadilan, M65, or vehicle for 21 days.
Maxadilan suppressed feeding and enhanced water intake significantly for the first several days. After that period,
maxadilan treatment continued to promote food and water intake. Long-term administration of
maxadilan led to an increase in
body weight (P<0.01), decrease in body fat (P<0.01), down-regulation of basal plasma
glucose (P<0.01), upregulation of basal plasma
insulin (P<0.01) and improved
glucose tolerance (P<0.01) and
insulin sensitivity (P<0.01). An elevation in plasma
LDL (P<0.01) was also observed in the
maxadilan group. However, M65 displayed no significant adverse effects on the aforementioned parameters except basal plasma
glucose (P<0.05). The significant changes induced by
maxadilan indicate that the
PAC1 receptor plays multiple key roles in carbohydrate metabolism, lipid metabolism and energy homeostasis in mice.