A growth hormone (GH) analog that antagonizes the lipolytic effect but retains full insulin-like (antilipolytic) activity of GH.
An analog of bovine growth hormone (bGH-M8: [Leu117, Arg119, Asp122]-bGH) with an idealized amphiphilic third alpha-helix has been proposed to be a functional antagonist of GH. In accordance with this proposition, bGH-M8 profoundly inhibited bGH-stimulated lipolysis by chicken adipose tissue in vitro. bGH-M8 alone was a weak agonist in the lipolytic assay (1.9% the potency of bGH). The present evidence indicates that bGH-M8 is a competitive antagonist of the lipolytic action of GH based upon the following results: (i) increasing concentrations of bGH-M8 (antagonist) produce progressively greater inhibition of GH-stimulated lipolysis; (ii) increasing concentrations of bGH (agonist) are capable of overcoming this antagonism; and (iii) Schild plot analysis (slope = -0.94) suggests a receptor antagonist with an equilibrium dissociation constant (KB) of 4.54 nM. In contrast to the antagonistic effects of bGH-M8 on bGH-stimulated lipolysis, bGH-M8 retained full insulin-like ("antilipolytic") activity (i.e., inhibition of glucagon-induced lipolysis). bGH-M8 and bGH were similarly potent in eliciting antilipolytic effects in vitro. Moreover, the antilipolytic effects of bGH-M8 and bGH were additive. Therefore, the third alpha-helix (particularly residues 117, 119, and 122) of bGH contains major structural determinants for the lipolytic effects of GH. The ability of bGH-M8 to act as an antagonist for at least one action of GH (lipolysis) while being a full agonist for another (antilipolysis) suggests that different domains of GH are responsible for its various biologic activities, possibly involving different binding sites and/or signal transduction mechanisms.
Department of Animal Science Research, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110.
R M
RM
Campbell
W Y
WY
Chen
P
P
Wiehl
B
B
Kelder
J J
JJ
Kopchick
C G
CG
Scanes
D000818:Animals; D001667:Binding, Competitive; D002645:Chickens; D013006:Growth Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D007328:Insulin; C081726:somatotropin, leucyl(117)-arginyl(119)-aspartyl(122)-; D013006:Growth Hormone