Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats

Abstract

Figlewicz DP, Bennett JL, Aliakbari S, Zavosh A, Sipols AJ. Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats. Am J Physiol Regul Integr Comp Physiol 295: R388 -R394, 2008. First published June 4, 2008 doi:10.1152/ajpregu.90334.2008.-Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and mu opioidstimulated sucrose feeding-when administered into several insulinreceptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75 Ϯ 5% of paired control). However, although the mu opioid DAMGO, [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) mu opioid-stimulated sucrose feeding: sucrose intake was 53 Ϯ 8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner. food reward; ventral tegmental area; arcuate nucleus WE HAVE PREVIOUSLY REPORTED that insulin can act within the central nervous system (CNS) to decrease food reward, in addition to providing an energy regulatory signal at the medial hypothalamus (3,11,14,31). Intraventricular (IVT) insulin administration prevents the expression of a place preference conditioned to a high-fat food treat (11), decreases initial lick rates for preferred sucrose solutions in a lickometer task (42), and decreases sucrose self-administration (13) in rats that are not food deprived. Further, IVT insulin decreases performance in the lateral hypothalamic self-stimulation task, such that there is an increase in the electrical frequency threshold required to sustain the behavior (7). Collectively, these findings support the hypothesis that insulin can blunt brain reward activity, including the rewarding attributes of food. However, the specific CNS sites that mediate the actions of insulin in different behavioral paradigms evaluating food reward have not been determined.Both the caloric and the motivating aspects of a palatable food such as sucrose might contribute to its ingestion, or overingestion, and the CNS circuitries i...

The Glucagon-Like Peptide 1 (GLP-1) Analogue, Exendin-4, Decreases the Rewarding Value of Food: A New Role for Mesolimbic GLP-1 Receptors

“…At 24 h after injection, the VTA GLP-1R activation still potently (Ͼ50%) reduced chow intake and body weight gain at both doses tested, whereas NAc shell injection produced a small effect only on chow intake at the highest dose tested, potentially indicating differential sensitivity of those two sites to anorexic effects of GLP-1 stimulation. These results contrast with those obtained for insulin, in which a reduction in free-feeding and food-motivated behavior was modulated by a disparate receptor population (Figlewicz et al, 2008). Thus, the mesolimbic GLP-1Rs can contribute to both free-feeding and motivated behavior for palatable food.…”

“…Several brain areas provide likely targets for the effects of EX4 and include brainstem and hypothalamic GLP-1R-expressing nuclei previously shown to play a role in GLP-1 anorexia (Schick et al, 2003;Hayes et al, 2009) that project to the mesolimbic system (e.g., VTA). In fact, for another peripheral hormone, insulin, despite the presence of insulin receptors in the VTA, only the hypothalamic stimulation was effective in reducing food reward (Figlewicz et al, 2008). However, our data showing a suppression of operant responding with a direct VTA or NAc EX4 microinjection demonstrate a direct impact of EX4 on these mesolimbic areas.…”

Central nervous insulin administration before nocturnal sleep decreases breakfast intake in healthy young and elderly subjects

“…This effect was primarily caused by a drop in the consumption of carbohydrates. This finding ties in with experiments in rats indicating that insulin administration to the CNS reduces sugar intake (Figlewicz et al, 2008) and suggests that, in accordance with the major role of peripheral insulin for blood glucose regulation, the anorexigenic effect of the hormone on the brain might focus on carbohydrates. However, the relative paucity of available data in humans (Benedict et al, 2008;Hallschmid et al, 2012;Jauch-Chara et al, 2012) and animals (Woods et al, 1979;McGowan et al, 1992;Air et al, 2002;Clegg et al, 2003Clegg et al, , 2006 at the moment does not permit sound conclusions on macronutrient-specific effects of brain insulin on eating behavior (for review see Kullmann et al, 2016;Lee et al, 2016).…”

High-fat diets induce a rapid loss of the insulin anorectic response in the amygdala

“…However, it is in the same range as the dose required for a feeding response to third ventricular insulin. We also note that Figlewicz and colleagues (15) likewise found that a dose of 5 mU insulin directly into the ventral tegmental area was ineffective in reducing food intake. There could be a number of explanations for the need for such high doses for the anorectic behavioral response compared with the lower doses that induce an acute short-lived signaling response.…”

“…On the day of testing, 3 h prior to lights off, the food cups were removed from the cages, and the rats were injected with vehicle (saline) or insulin into the amygdala (Humulin R; Eli Lilly, Indianapolis IN). The doses of insulin used in our experiments were selected based on previous experiments taken from the literature for intracerebroventricular or intraneuropil administrations (15,16,40,46). Solutions were prepared fresh before injection.…”