Thermogenesis and weight control.

Abstract

Compound LY104119, [R-(R*,S*)]-4-[3-[(2-hydroxy-2-phenylethyl)amino]butyl]benzamide monohydrochloride, was found to be a potent beta-agonist in the mouse. Its Ki for displacing the binding of (-)-3H-dihydroalprenolol to beta-receptors on the lung membranes from either viable yellow obese mice (VY/WfL-Avy/a) or their corresponding normal controls (VY/WfL-a/a) was 3 X 10(-7) M, comparable to that of isoproterenol which was 2 X 10(-7) M. LY104119 increased the concentration of cyclic AMP in adipose tissue, stimulated lipolysis in vitro and in vivo and the expiration of CO2 in vivo. When given s.c. or p.o., LY104119 reduced the body weight of Avy/a mice without altering the food consumption. The loss of triacylglycerol accounted for a major portion of the weight loss and the weight was recovered after the treatment was withdrawn. When fed in the diet, LY104119 reduced the weight of Avy/a mice and caused a moderate increase of food intake. Thermogenesis (whole body heat production) of the treated mice increased. An elevated level of hepatic glucokinase activity regularly found in these mice was almost normalized to the level measured in normal mice. The kinetic properties of the beta-receptors were not altered, but the number of beta-receptors on lung membranes was reduced about 25 percent. The lipolytic response of epididymal adipose tissue to LY104119 or isoproterenol, however, was not changed. When slightly overweight a/a mice were treated with LY104119 in the diet, they lost weight, but a similar treatment of normal-weight a/a mice caused a loss of only a small amount of carcass triacylglycerol without affecting the body weight. These normal-weight a/a mice were able to maintain their weight by an exorbitant increase of food intake. When this large increase of food consumption was not allowed, ie by being restricted to normal amounts of food intake, normal-weight a/a mice fed LY104119 did lose weight. Thermogenesis increased in all LY104119-treated a/a mice. However, the increase in the LY104119-treated but diet-restricted a/a mice was smaller than that in the LY104119-treated a/a mice fed ad libitum. We conclude from these observations that: Compound LY104119 was able to decrease weight in Avy/a mice apparently through the stimulation of the beta-adrenergic system. The metabolic responses to LY104119 were not different in obese Avy/a mice and normal a/a mice. The difference between the Avy/a mice and the a/a mice was in their ability to increase their food consumption to compensate for the energy loss caused by LY104119.