Objective

To regulate food intake, our brain constantly integrates external cues, such as the incentive value of a potential food reward, with internal state signals, such as hunger feelings. Incentive motivation refers to the processes that translate an expected reward into the effort spent to obtain the reward; the magnitude and probability of a reward involved in prompting motivated behaviour are encoded by the dopaminergic (DA) midbrain and its mesoaccumbens DA projections. This type of reward circuity is particularly sensitive to the metabolic state signalled by peripheral mediators, such as insulin or glucagon-like peptide 1 (GLP-1). While in rodents the modulatory effect of metabolic state signals on motivated behaviour is well documented, evidence of state-dependent modulation and the role of incentive motivation underlying overeating in humans is lacking.

Methods

In a randomised, placebo-controlled, crossover design, 21 lean (body mass index [BMI] < 25 kg/m²) and 16 obese (BMI³ 30 kg/m²) volunteer participants received either liraglutide as a GLP-1 analogue or placebo on two separate testing days. Incentive motivation was measured using a behavioural task in which participants were required to exert physical effort using a handgrip to win different amounts of food and monetary rewards. Hunger levels were measured using visual analogue scales; insulin, glucose, and systemic insulin resistance as assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) were quantified at baseline.

Results

In this report, we demonstrate that incentive motivation increases with hunger in lean humans (F_(1,42) = 5.31, p = 0.026, β = 0.19) independently of incentive type (food and non-food reward). This effect of hunger is not evident in obese humans (F_(1,62) = 1.93, p = 0.17, β = −0.12). Motivational drive related to hunger is affected by peripheral insulin sensitivity (two-way interaction, F_{(1, 35)} = 6.23, p = 0.017, β = −0.281). In humans with higher insulin sensitivity, hunger increases motivation, while poorer insulin sensitivity dampens the motivational effect of hunger. The GLP-1 analogue application blunts the interaction effect of hunger on motivation depending on insulin sensitivity (three-way interaction, F_{(1, 127)} = 5.11, p = 0.026); no difference in motivated behaviour could be found between humans with normal or impaired insulin sensitivity under GLP-1 administration.

Conclusion

We report a differential effect of hunger on motivation depending on insulin sensitivity. We further revealed the modulatory role of GLP-1 in adaptive, motivated behaviour in humans and its interaction with peripheral insulin sensitivity and hunger. Our results suggest that GLP-1 might restore dysregulated processes of midbrain DA function and hence motivational behaviour in insulin-resistant humans.

中文翻译：

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GLP-1 和饥饿根据人类的胰岛素敏感性调节激励动机

客观的

为了调节食物摄入量，我们的大脑不断将外部线索（例如潜在食物奖励的激励值）与内部状态信号（例如饥饿感）相结合。激励动机是指将预期奖励转化为获得奖励所付出的努力的过程；参与激励动机行为的奖励的幅度和概率由多巴胺能 (DA) 中脑及其中伏隔 DA 预测编码。这种类型的奖赏回路对由外周介质（例如胰岛素或胰高血糖素样肽 1 (GLP-1)）发出的代谢状态特别敏感。虽然在啮齿类动物中，代谢状态信号对动机行为的调节作用有据可查，

方法

在随机、安慰剂对照、交叉设计中，21 名瘦肉（体重指数 [BMI] < 25 kg/m ²）和 16 名肥胖（BMI³ 30 kg/m ²）志愿者接受利拉鲁肽作为 GLP-1 类似物或安慰剂在两个不同的测试日。激励动机是使用行为任务来衡量的，在该任务中，参与者被要求使用手柄进行体力劳动以赢得不同数量的食物和金钱奖励。使用视觉模拟量表测量饥饿水平；通过胰岛素抵抗的稳态模型评估 (HOMA-IR) 评估的胰岛素、葡萄糖和全身胰岛素抵抗在基线进行量化。

结果

在本报告中，我们证明了激励动机随着饥饿而增加（F _(1,42)  = 5.31, p  = 0.026, β = 0.19）与激励类型（食物和非食物奖励）无关。这种饥饿效应在肥胖人群中并不明显（F _(1,62)  = 1.93, p  = 0.17, β = -0.12）。与饥饿相关的动机受到外周胰岛素敏感性的影响（双向相互作用，F _{(1, 35)}  = 6.23, p = 0.017，β = -0.281）。在胰岛素敏感性较高的人中，饥饿会增加动机，而胰岛素敏感性较差的人会抑制饥饿的动机效应。GLP-1 类似物应用根据胰岛素敏感性减弱饥饿对动机的相互作用影响（三向相互作用，F _{(1, 127)}  = 5.11, p  = 0.026）；在 GLP-1 给药下，胰岛素敏感性正常或受损的人之间没有发现动机行为的差异。

结论

我们报告了饥饿对动机的不同影响，这取决于胰岛素敏感性。我们进一步揭示了 GLP-1 在人类适应性、动机行为中的调节作用及其与外周胰岛素敏感性和饥饿的相互作用。我们的结果表明 GLP-1 可能会恢复中脑 DA 功能的失调过程，从而恢复胰岛素抵抗人类的动机行为。