Universität zu Köln

Kretschmer, Alina Chloé ORCID: 0000-0002-6323-1928 (2021). Incentive motivation in humans is modulated by GLP-1 and hunger depending on insulin sensitivity. PhD thesis, Universität zu Köln.

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Abstract

In everyday life, our brain constantly needs to integrate external cues – such as the rewarding value of a potential food reward – with internal signals – such as hunger feelings – in order to decide which rewards are worth spending effort for and to guide our food intake behaviour. Hence, metabolic signals from the periphery need to reach our brain and interact with the circuitries controlling our motivation to spend effort in order to obtain certain food rewards. Incentive motivation refers to the processes that translate the rewarding value of external cues into physical effort to obtain the reward. The dopaminergic midbrain and dopaminergic mesoaccumbens projections encode the amount and the probability of rewards, that initiate motivated behaviour. The dopaminergic midbrain and its projections are also particularly sensitive to the metabolic state, that is reflected by peripheral signals such as insulin and GLP-1. Animal studies have already assessed the modulatory effect of metabolic state signaling on motivated behaviour. However, in humans, we still lack information about state-dependent modulation of reward-related motivated behaviour and its contribution to obesity. The aim of this study was to assess the impact of metabolic signals, notably of GLP-1, insulin sensitivity and hunger, on the regulation of reward-related motivated behaviour in humans. In a randomized, placebo-controlled, crossover study, 21 lean (body mass index, BMI, < 25 kg/m2) and 16 obese (BMI > 30 kg/m2) participants received either liraglutide as GLP-1 analogue or placebo on two separate testing days. Incentive motivation was measured using a computer experiment in which participants were required to exert physical effort using a handgrip in order to win different amounts of food and monetary reward. 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 in a blood draw before the task. Our results revealed that incentive motivation increases with hunger in lean humans (F(1,42) = 5.31, p = 0.026, β = 0.19), whereas hunger did not affect motivation in obese participants (F(1,62) = 1.93, p = 0.17, β = -0.12). We further showed that the effect of hunger on motivation depended on the peripheral insulin sensitivity of the participants (two way interaction, F(1, 35) = 6.23, p = 0.017, β = -0.281). In humans with higher insulin sensitivity, hunger increased motivation, while poorer insulin sensitivity decreased the motivational effect of hunger. Notably, this holds true for both food and monetary reward. GLP-1 analogue application blunted the insulin-sensitivity-dependent effect of hunger on motivation (three-way interaction, F(1, 127) = 5.11, p = 0.026); i.e., GLP-1 analogue application normalized motivated behaviour of insulin resistant participants so that no difference between insulin resistant and insulin sensitive participants could be detected any more. In order to explain these behavioural results, we suggest a model of the underlying neural processes. As incentive motivation was not affected by the type of reward in our study, we suggest motivation to be regulated very basally on the level of the dopaminergic midbrain rather than on a cortical level. We further provide support for the existing thesis that insulin sensitivity is a better predictor of altered DA signaling than the BMI. In summary, we here report a differential effect of hunger on motivation to obtain food and non-food reward depending on insulin sensitivity. We further demonstrate that GLP-1 plays a regulatory role in adaptive, motivated behaviour in humans, and is able to restore dysregulated processes of the dopaminergic midbrain and hence motivational behaviour in insulin resistant humans.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kretschmer, Alina Chloé kretschmeralina@gmx.de orcid.org/0000-0002-6323-1928 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-640633
DOI:	10.1016/j.molmet.2021.101163
Date:	March 2021
Publisher:	Elsevier
Place of Publication:	Journal of Molecular Metabolism
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Poliklinik für Endokrinologie, Diabetologie und Präventivmedizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Glucagon-like peptide-1 English Regulation of motivational behaviour English Insulin sensitivity English Obesity English
Date of oral exam:	24 August 2022
Referee:	Name Academic Title Brüning, Jens C. Universitätsprofessor Korotkova, Tatjana Universitätspprofessorin
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/64063