Leptin Regulates Energy Balance and Motivation Through Action at Distinct Neural Circuits

Abstract

BACKGROUND-Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine.

Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine

“…This system is responsive not only to a variety of glutamatergic inputs from local (Dobi et al, 2010) and distal (Geisler et al, 2007) neuronal sources, but also to a number of state variables mediated by blood-borne factors including leptin (Figlewicz et al, 2003;Krugel et al, 2003;Hommel et al, 2006;Liu et al, 2011;Thompson and Borgland, 2013). Leptin is an endogenous inhibitor of food reward (Figlewicz et al, 2007;Domingos et al, 2011) that has both direct (Fulton et al, 2006a;Krugel et al, 2003;Leinninger et al, 2009;Davis et al, 2011;Domingos et al, 2011) and indirect (Leinninger et al, 2009) effects on brain reward function and that is depressed in heroin addicts (Housová et al, 2005) and fluctuates abnormally during craving for alcohol (Kiefer et al, 2005) or nicotine (al 'Absi et al, 2011).…”

High fat/carbohydrate ratio but not total energy intake induces lower striatal dopamine D2/3 receptor availability in diet-induced obesity

“…Midbrain leptin receptors may have a role, as they mediate the decrease in extracellular dopamine levels in the nucleus accumbens (NAcc) by a HF diet. 6 In addition, knockdown of the dopamine D 2 receptor in the striatum is associated with increased reward deficiency and compulsive eating behavior in rats.1 This can be related to the alternative hypothesis that low DRD 2/3 levels might be a downregulation due to overstimulation of the dopamine system by repetitive food intake in obesity. 4 It remains unclear though whether increased total energy intake by high-energy diets or specific dietary components (for example, saturated fat, carbohydrates) underlie the induction of lower striatal DRD 2/3 levels.…”

“…12 Moreover, diets high in fat reduce dopamine levels and decrease dopamine release in the NAcc. 6,13,14 Leptin might have a role in this mechanism, 6,15 although a role for the degree of insulin resistance is also possible.14 However, decreased dopamine release cannot directly explain DRD 2/3 downregulation, because, in case of low extracellular dopamine levels, one would expect a compensatory DRD 2/3 upregulation. So, the effects of diet-induced obesity on the mesolimbic dopaminergic system are more complex than can be explained by this leptin or insulin resistance pathway.…”

“…Midbrain leptin receptors may have a role, as they mediate the decrease in extracellular dopamine levels in the nucleus accumbens (NAcc) by a HF diet. 6 In addition, knockdown of the dopamine D 2 receptor in the striatum is associated with increased reward deficiency and compulsive eating behavior in rats.…”

Transregionaler Sonderforschungsbereich 134: „Ingestive Behaviour: Homeostasis & Reward“

“…Eine Administration von Leptin direkt in die VTA führt zu einer Erniedrigung der lokalen neuronalen Aktivität, was wiederum die Nahrungsaufnahme inhibiert. Umgekehrt steigert eine siRNA-vermittelte Ausschaltung des Leptinrezeptors in dieser Region den Appetit -insbesondere für fettreiche Nahrung [ 2 ]. Ähnliche Daten liegen für andere wichtige periphere metabolische Signalpeptide wie Insulin oder Ghrelin vor [ 4 , 7 ].…”