Mechanisms of Amylin/Leptin Synergy in Rodent Models

Abstract

The present studies aimed to identify mechanisms contributing to amylin/leptin synergy in reducing body weight and adiposity. We reasoned that if amylin/leptin harnessed complementary neuronal pathways, then in the leptin-sensitive state, amylin should augment leptin signaling/binding and that in the absence of endogenous amylin, leptin signaling should be diminished. Amylin (50 microg/kg, ip) amplified low-dose leptin-stimulated (15 microg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 microg/kg x d) or leptin (125 microg/kg x d) infusion to lean rats decreased 28-d food intake (14 and 10%, respectively), body weight (amylin by 4.3%, leptin by 4.9%), and epididymal fat (amylin by 19%, leptin by 37%). Amylin/leptin co-infusion additively decreased food intake (by 26%) and reduced body weight (by 15%) and epididymal fat (by 78%; all P < 0.05 vs. all groups) in a greater than mathematically additive manner, consistent with synergy. Amylin increased leptin binding within the ventromedial hypothalamus (VMN) by 35% and dorsomedial hypothalamus by 47% (both P < 0.05 vs. vehicle). Amylin/leptin similarly increased leptin binding in the VMN by 40% and ARC by 70% (P < 0.05 vs. vehicle). In amylin-deficient mice, hypothalamic leptin receptor mRNA expression was reduced by 50%, leptin-stimulated phosphorylated signal transducer and activator of transcription-3 within ARC and VMN was reduced by 40%, and responsiveness to leptin's (1 mg/kg x d for 28 d) weight-reducing effects was attenuated (all P < 0.05 vs. wild-type controls). We suggest that amylin/leptin's marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways and further point to the integrated neurohormonal therapeutic potential of amylin/leptin agonism in obesity.

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

“…Means with different letters are significantly different (p<0.05), whereas means with the same letters are not different from each other. A, amylin; C, non-treated control; L, leptin It has been proposed that co-administration of leptin and amylin in mice in vivo results in a multiplicative effect on STAT3 phosphorylation in the hypothalamus as compared with treatment with either of the hormones separately [36]. Also, we have demonstrated for the first time that leptin and amylin increase STAT3/AMPK/ERK signalling and that the effects of these two hormones are similar in magnitude, peaking at about the same time in mouse GT1-7 hypothalamic and C 2 C 12 muscle cell lines in vitro [35] and in human adipose tissues and peripheral blood mononuclear cells ex vivo [30].…”

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. The potential mechanisms of this interaction have been summarized recently.…”

“…Amylin strongly enhanced leptin signaling specifically in the ventromedial hypothalamus, and this was also confirmed under in vitro conditions. 81,85,[95][96][97] Amylin also increased leptin binding in the ventromedial hypothalamus and other hypothalamic sites, for example, the dorsomedial hypothalamus, 85 whereas leptin receptor expression was reduced in the mediobasal hypothalamus in amylin-deficient mice. 85 A recent study indicated that interleukin-6 (IL-6) seems to be involved in the leptin-sensitizing effect of amylin.…”

“…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.…”

“…The potential mechanisms of this interaction have been summarized recently. 85,93,94 Briefly, most data indicate that the hypothalamus, and in particular the ventromedial hypothalamus, is critically involved in this interaction. Amylin strongly enhanced leptin signaling specifically in the ventromedial hypothalamus, and this was also confirmed under in vitro conditions.…”