Melanocortin-4 Receptors Expressed by Cholinergic Neurons Regulate Energy Balance and Glucose Homeostasis

Abstract

Summary Melanocortin-4-receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brainstem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin mediated-suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4Rs expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis.

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…To assess the effect of SIRT1 on motor neurons, we examined several previously described mouse lines that can be engineered to overexpress or inactivate SIRT1 in motor neurons (Cohen, Supinski, Bonkowski, Donmez, & Guarente, 2009; Firestein et al, 2008; Rossi et al, 2011). Transgenic mice were created by breeding animals with a floxed‐stop cassette upstream of Sirt1 with mice expressing Cre recombinase under the choline acetyltransferase promoter.…”

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…Striatal ACh and FS acquire their phenotype during the first 2–3 postnatal weeks in rodents along with the expression of specific markers such as choline acetyltransferase (ChAT, Ach; Phelps, Brady, & Vaughn, 1989) and parvalbumin (PV, FS; Schlösser, Klausa, Prime, & Bruggencate, 1999). To conditionally delete Smo in ACh or FS, we selected the ChAT‐Cre (Rossi et al, 2011) and PV‐Cre (Hippenmeyer et al, 2005) lines (Figure 2a,e). To validate the specificity of these mouse lines, we used the Rosa26R‐YFP reporter mouse.…”

“…All experiments were performed according to institutional guidelines approved by the ethics committee of the Hospital Universitario Virgen del Rocio and the European Community (Council Directive 86/609/EEC). Pv Cre (Hippenmeyer et al, 2005), Chat Cre (Rossi et al, 2011), Smo Flox (Long, Zhang, Karp, Yang, & McMahon, 2001), Shh Flox (Lewis et al, 2001), Rosa26R‐Tomato (Madisen et al, 2010), and Rosa26R‐YFP mice (Srinivas et al, 2001) were obtained from Jackson Laboratory (Stocks numbers 8,069, 6,410, 4,526, 4,293, 7,909, and 6,148) and were maintained on their genetic background (B6;129P2, C57BL/6, 129X1/SvJ, and C57BL/6J). Breeding previous lines, we generated Pv Cre/+ ; Smo loxP/loxP (PV‐Smo), Chat Cre/+ ; Smo loxP/loxP (ChAT‐Smo), Pv Cre/+ ; Shh loxP/loxP (PV‐Shh), and Chat Cre/+ ; Shh loxP/loxP (ChAT‐Shh).…”

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

“…MC4R has been associated with key components of nutrient absorption, lipid metabolism, energy expenditure, thermogenesis, adiposity, insulin secretion, food intake, and appetite (Adan et al 2006). Moreover, the MC pathway interacts with other key hormones or pathways such as leptin, 5-HT (Zhou et al 2007), NPY, AGRP, POMC (Biebermann et al 2012), and ANS (Rossi et al 2011;Sohn et al 2013) in the hypothalamus and brainstem (Loos 2011), GLP-1 pathway (Gautron et al 2010), CCK, and vagal afferent fibers (Guan et al 2012).…”