RGD Reference Report - Vascular effects of deletion of melanocortin-4 receptors in rats. - Rat Genome Database

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Vascular effects of deletion of melanocortin-4 receptors in rats.

Authors: Stepp, David W  Osakwe, Christabell C  Belin de Chantemele, Eric J  Mintz, James D 
Citation: Stepp DW, etal., Physiol Rep. 2013 Nov;1(6):e00146. doi: 10.1002/phy2.146. Epub 2013 Nov 13.
RGD ID: 13825242
Pubmed: PMID:24400148   (View Abstract at PubMed)
PMCID: PMC3871461   (View Article at PubMed Central)
DOI: DOI:10.1002/phy2.146   (Journal Full-text)

Obesity is a major cause of hypertension, but links between the obese and hypertensive states remain incompletely understood. A major component of cardiovascular function in obese individuals is a state of sympathoactivation. A postulated mechanism of this sympathoactivation is the activation of specific classes of neurons commonly associated with metabolic control, which also affect sympathetic outflow to cardiovascular targets. One class of neurons is characterized by expression of melanocortin-4 receptors (MC4R) which are activated by metabolic signals such as leptin and insulin. In this study, we examined the effects of deletion of MC4R in a novel rat model. MC4R knockout (KO) rats are obese and profoundly insulin resistant without frank diabetes. Despite these conditions, MC4R KO rats are normotensive. Moderate bradycardia and significant increases in peripheral resistance were evident in MC4R KO rats. To determine if the dissociation between hypertension and obesity was associated with changes in vascular function, in vitro reactivity to vasoactive agents and in vivo reactivity to sympathetic blockade were examined. Vasodilator function was not affected by obesity in MC4R KO rats. Reactivity to phenylephrine was reduced, suggesting desensitization of adrenergic signaling. In response to ganglionic blockade with mecamylamine, blood pressure and hindlimb resistance fell more in MC4R KO rats, suggesting that sympathoactivation of the vascular was still evident, despite the absence of hypertension. These findings suggest that obesity causes sympathoactivation of the vasculature despite the absence of MC4R. Dissociation of obesity from hypertension in this model may reflect more renal mechanisms of blood pressure control.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MC4RHumanBradycardia  ISOMc4r (Rattus norvegicus) RGD 
Mc4rRatBradycardia  IMP  RGD 
Mc4rMouseBradycardia  ISOMc4r (Rattus norvegicus) RGD 
MC4RHumanInsulin Resistance  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rRatInsulin Resistance  IMP DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rMouseInsulin Resistance  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rm1HubrRatInsulin Resistance  IMP DNA:nonsense mutation:cds:p.K314XRGD 
WI-Mc4rm1HubrRatInsulin Resistance  IMP DNA:nonsense mutation:cds:p.K314XRGD 
MC4RHumanobesity  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rRatobesity  IMP DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rMouseobesity  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rm1HubrRatobesity  IMP DNA:nonsense mutation:cds:p.K314XRGD 
WI-Mc4rm1HubrRatobesity MODEL: spontaneousIMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mc4rRatdecreased heart rate  IMPcholinergic antagonistcompared with WI-MC4r^m1HubrRGD 
Mc4rRatdecreased heart rate  IMP  RGD 
Mc4rm1HubrRatdecreased heart rate  IMP  RGD 
Mc4rm1HubrRatdecreased heart rate  IMPcholinergic antagonistcompared with WI-MC4r^m1HubrRGD 
WI-Mc4rm1HubrRatdecreased heart rate  IMPcholinergic antagonistcompared with WI-MC4r^m1HubrRGD 
WI-Mc4rm1HubrRatdecreased heart rate  IMP compared with Wistar/CrlRGD 
Mc4rRatdecreased mean systemic arterial blood pressure  IMPmecamylamine RGD 
Mc4rm1HubrRatdecreased mean systemic arterial blood pressure  IMPmecamylamine RGD 
WI-Mc4rm1HubrRatdecreased mean systemic arterial blood pressure  IMPmecamylamine RGD 
Mc4rRatdecreased vasoconstriction  IMPphenylephrine RGD 
Mc4rm1HubrRatdecreased vasoconstriction  IMPphenylephrine RGD 
WI-Mc4rm1HubrRatdecreased vasoconstriction  IMPphenylephrine RGD 
Mc4rRatincreased body weight  IMP  RGD 
Mc4rm1HubrRatincreased body weight  IMP  RGD 
WI-Mc4rm1HubrRatincreased body weight  IMP  RGD 
Mc4rRatincreased circulating cholesterol level  IMP  RGD 
Mc4rm1HubrRatincreased circulating cholesterol level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating cholesterol level  IMP  RGD 
Mc4rRatincreased circulating free fatty acids level  IMP  RGD 
Mc4rm1HubrRatincreased circulating free fatty acids level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating free fatty acids level  IMP  RGD 
Mc4rRatincreased circulating insulin level  IMP  RGD 
Mc4rm1HubrRatincreased circulating insulin level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating insulin level  IMP  RGD 
Mc4rRatincreased circulating leptin level  IMP  RGD 
Mc4rm1HubrRatincreased circulating leptin level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating leptin level  IMP  RGD 
Mc4rRatincreased circulating triglyceride level  IMP  RGD 
Mc4rm1HubrRatincreased circulating triglyceride level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating triglyceride level  IMP  RGD 
Mc4rRatincreased fluid intake  IMP  RGD 
Mc4rm1HubrRatincreased fluid intake  IMP  RGD 
WI-Mc4rm1HubrRatincreased fluid intake  IMP  RGD 
Mc4rRatincreased glycosylated hemoglobin level  IMP  RGD 
Mc4rm1HubrRatincreased glycosylated hemoglobin level  IMP  RGD 
WI-Mc4rm1HubrRatincreased glycosylated hemoglobin level  IMP  RGD 
Mc4rRatincreased heart weight  IMP  RGD 
Mc4rm1HubrRatincreased heart weight  IMP  RGD 
WI-Mc4rm1HubrRatincreased heart weight  IMP  RGD 
Mc4rRatincreased kidney weight  IMP  RGD 
Mc4rm1HubrRatincreased kidney weight  IMP  RGD 
WI-Mc4rm1HubrRatincreased kidney weight  IMP  RGD 
Mc4rRatincreased systemic vascular resistance  IMP  RGD 
Mc4rm1HubrRatincreased systemic vascular resistance  IMP  RGD 
WI-Mc4rm1HubrRatincreased systemic vascular resistance  IMP  RGD 
Mc4rRatincreased vasoconstriction  IMPpotassium chloride solution RGD 
Mc4rm1HubrRatincreased vasoconstriction  IMPpotassium chloride solution RGD 
WI-Mc4rm1HubrRatincreased vasoconstriction  IMPpotassium chloride solution RGD 
Mc4rRatpolyphagia  IMP  RGD 
Mc4rm1HubrRatpolyphagia  IMP  RGD 
WI-Mc4rm1HubrRatpolyphagia  IMP  RGD 
Mc4rRatpolyuria  IMP  RGD 
Mc4rm1HubrRatpolyuria  IMP  RGD 
WI-Mc4rm1HubrRatpolyuria  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mc4r  (melanocortin 4 receptor)
Mc4rm1Hubr  (melanocortin 4 receptor; ENU induced mutation 1, Hubr)

Genes (Mus musculus)
Mc4r  (melanocortin 4 receptor)

Genes (Homo sapiens)
MC4R  (melanocortin 4 receptor)

WI-Mc4rm1Hubr  (NA)

Additional Information