Combined amylin–leptin treatment lowers blood pressure and adiposity in lean and obese rats

Abstract

Objective: To examine the cardiovascular effects of combined amylin (AMN) and leptin (LEP) treatment in lean and obese rats. Research design: Rats were instrumented for telemetry and given LEP (300 mg kg -1 day -1 ), AMN (100 mg kg -1 day -1 ), AMN þ LEP or vehicle (VEH; 0.9% normal saline) via a subcutaneous mini-osmotic pump for 7 days. The VEH group was subdivided into ad libitum fed and pair-fed to the amount of food AMN þ LEP animals ate daily. Rats were housed in metabolic chambers for analysis of cardiovascular physiology and metabolism. Subjects: Male Fisher 344 Â Brown Norway (FBNF1; Harlan; age ¼ 3-5 months; n ¼ 72) rats were placed on standard rodent chow (LEAN, n ¼ 41) or moderately high-fat diet (OBESE; n ¼ 31) to produce obesity. Results: AMN þ LEP potently reduced food intake (LEAN: 57% OBESE: 59%) and abdominal fat mass (LEAN: 56% OBESE: 41%). Pair-fed rats displayed bradycardia and metabolic suppression. In contrast, AMN þ LEP increased heart rate and oxygen consumption above levels in LEP or AMN-treated rats. LEP reduced blood pressure in both lean and obese rats but AMN had no effect. LEP-induced reductions in blood pressure were not altered by AMN þ LEP treatment. Thus, AMN þ LEP treatment decreased food intake, body fat and blood pressure in lean and obese rats. Conclusion: We conclude that the potent anti-adiposity actions of AMN þ LEP are due in part to prevention of the bradycardia and metabolic suppression typically observed with negative energy balance. Furthermore, the hypotensive actions of peripheral LEP treatment are observable in spite of the potent AMN þ LEP activation of anorexic and thermogenic mechanisms in the central nervous system.

Control of energy homeostasis by amylin

“…Interestingly, body fat loss was more in the amylin/leptin-treated rats than in the pair-fed controls, which was also observed in the study by Seth and colleagues [171]. This was most likely due to the decrease in energy expenditure in pair-fed rats which was completely prevented in the amylin/leptin group [108,109,171]. During weight loss, the respiratory quotient was low in both the amylin/leptin and the pair-fed groups [108,109,144,171,172], indicating preferential oxidation of fat.…”

“…The combinations produced weight losses of up to 15% [144,172]; most of the body weight loss was due to reduced eating because rats pair-fed to the amylin/leptin group lost similar amounts of weight [144]. Interestingly, body fat loss was more in the amylin/leptin-treated rats than in the pair-fed controls, which was also observed in the study by Seth and colleagues [171]. This was most likely due to the decrease in energy expenditure in pair-fed rats which was completely prevented in the amylin/leptin group [108,109,171].…”

“…Follow-up experiments using several dose combinations confirmed the synergistic effect of amylin and leptin on eating and adiposity [108,109,171]. The combinations produced weight losses of up to 15% [144,172]; most of the body weight loss was due to reduced eating because rats pair-fed to the amylin/leptin group lost similar amounts of weight [144].…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…81 The effect of the amylin/leptin combination on energy balance appeared to be paralleled by a preferential oxidation of fat as indicated by the low respiratory quotient in both the amylin/leptin and pair-fed groups; 81,[84][85][86] importantly, the lower respiratory quotient was still evident in amylin/leptin coinjected animals during the weight stable phase and not only during weight loss like in the pair-fed group. 81,85,[90][91][92] All effects combined, the amylin/leptin combination treatment prevented the suppression of energy metabolism that is typically seen in situations of negative energy balance which may, for example, be induced by simple dieting.…”

“…81 In other words, amylin, which itself is still effective in obese rats, 3,82,83 reduced eating and body weight significantly more when leptin was co-administered with amylin. 81,[84][85][86] The effect of amylin on leptin's action and leptin sensitivity appeared to be specific to amylin 81 because the effects were not seen to the same extent with the GLP-1 analog AC3174, 81 or when infusions of leptin were combined with the GLP-1 receptor agonist exendin-4. 87 Leptin combined with GLP-1 analogs did produce the stronger effects on eating and body weight than single compounds, but the interaction seemed to be (mathematically) additive rather than synergistic.…”