Abstract
Background
Leptin is well known as a satiety hormone to regulate energy balance by inhibiting hunger. However, an inability for leptin to act normally occurs in obesity, a phenomenon named leptin resistance. Considerable attention has focused on leptin resistance in the hypothalamus. However there has been relatively little attention on vagal afferents, which transmit satiety signals to the CNS. Interestingly, selective knockout of leptin receptor in vagal afferent neurons prevents high fat diet-induced weight gain (de Lartigue, 2014), whereas underlying mechanisms remain unknown.
Aims
Thus, this study aimed to examine the effects of leptin on satiety signaling via vagal afferents.
Methods
All experiments were performed on male C57/BL6 mice in accordance with the guideline of Canadian Council for Animal Care. Obese and control mice were fed on a high (HFF, 60% calories from fat) and low (LFF, 10%) fat diet respectively. Membrane excitability of nodose neurons was assessed by whole cell patch clamp. Afferent discharge was recorded from jejunal mesenteric nerves.
Results
Incubation of serum from HFF mice overnight resulted in lower excitability of nodose neurons from normal mice compared to LFF mice serum, evidenced by increased rheobase (78.6 ± 16.1 vs. 32.7 ± 5.1 pA, P<0.01, N≥14, unpaired t-test) and reduced number of action potentials at twice rheobase (1.5 ± 0.2 vs. 4.0 ± 0.6 P<0.001, N=14, unpaired t-test). These differences were absent in nodose neurons from leptin receptor deficient mice. Leptin’s inhibitory effect on nodose neuron excitability was blocked by zoledronic acid, an inhibitor of suppressor of cytokine signalling-3 (SOCS3). Effect of leptin on afferent signaling induced by CCK was examined in LFF and HFF mouse jejunum. Co-application of leptin and CCK moderately potentiated afferent response to CCK in LFF mice (P<0.05, one-way ANOVA, N=7), whereas leptin inhibited CCK signaling dose-dependently in HFF mice (P<0.01, one-way ANOVA, N=7). The inhibitory effects of leptin on CCK signaling was blocked by zoledronic acid (P<0.05, Bonferroni test, N=7).
Conclusions
These data suggest that leptin’s anorexigenic actions were switched to orexigenic in obesity, and this will provide new strategies for obesity treatment.
Funding Agencies
CIHR