Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss

Abstract

ObjectiveAppetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised of melanocortin neurons. The role of neural melanocortin-3 receptors (MC3R) in mediating these responses is enigmatic. Mc3r knockout mice exhibit a paradoxical phenotype of obesity and reduced feeding-related behaviors in situations of nutrient scarcity. Here we examined whether MC3Rs expressed in mesolimbic neurons regulate feeding-related motivational responses.MethodsInteractions between Mc3r genotype, cognitive function and energy balance on food self-administration were assessed using operant conditioning with fixed- and progressive ratio (FR1/PR1) settings. Inhibition of Mc3r transcription by a loxP-flanked transcriptional blocker (TB) in C57BL/6JN mice (Mc3rTB/TB) was reversed in mesolimbic neurons using DAT-Cre (DAT-MC3R).ResultsCaloric restriction (CR) caused 10–15% weight loss and increased motivation to acquire food rewards during training sessions. c-Fos-expression in the nucleus accumbens was increased 1 h following food presentation. While exhibiting weight loss, total food self-administration, enhanced motivation to self-administer food rewards in training sessions held during CR and c-Fos-activation in the nucleus accumbens following re-feeding were all markedly attenuated in Mc3rTB/TB mice. In contrast, cognitive abilities were normal in Mc3rTB/TB mice. Total food self-administration during FR1 sessions was not rescued in DAT-MC3R mice, however enhanced motivational responses to self-administer food rewards in PR1 conditions were restored. The nutrient-partitioning phenotype observed with Mc3r-deficiency was not rescued in DAT-MC3R mice.ConclusionsMesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning.

Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

“…As previously reported14, Mc3r TB/TB mice exhibited reduced self-administration of food rewards during training sessions in the lights-on period (Fig. 1H).…”

“…Based on the current results and previously published observations814, the identity and site of action for MC3Rs involved in regulating nutrient partitioning remains unclear.…”

“…Nuclear magnetic resonance (NMR, Bruker Minispec) was used to measure fat mass (FM), fat-free mass (FFM) and free H 2 O14.…”

Melanocortin‐3 Receptors Expressed on Agouti‐Related Peptide Neurons Inhibit Feeding Behavior in Female Mice

“…In Mc3r ‐deficient mice, AgRP +ve neurons exhibit a blunted increase in the expression of orexigenic neuropeptides (AgRP, NPY) during energy deficit . Rescuing Mc3r expression in dopaminergic neurons partially restores appetitive responses to energy deficit . MC3Rs expressed in Nkx2.1 +ve neurons restore normal regulation of AgRP +ve neurons and motivational responses to energy deficit.…”

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

“…Roger Cone’s group has reported that mice with inactivation of MC3R have greater anorexia and loss of lean tissues in response to lipopolysaccharide injection or tumor growth [32], as well as impaired feeding response to fasting [33], all consistent with a role for MC3R activation as stimulatory for energy intake and gain of lean mass. Data also suggest activation of MC3R is essential for proper alignment of metabolic responses during entrainment to restricted feeding regimens [34] and that MC3R in the limbic system is important for motivating feeding after energy restriction [35]. …”