RGD Reference Report - Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes. - Rat Genome Database

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Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Authors: Li, Ji-Yao  Wu, Xiaoyin  Lee, Allen  Zhou, Shi-Yi  Owyang, Chung 
Citation: Li JY, etal., J Neurophysiol. 2019 Mar 1;121(3):928-939. doi: 10.1152/jn.00413.2018. Epub 2019 Jan 16.
RGD ID: 597830031
Pubmed: PMID:30649980   (View Abstract at PubMed)
PMCID: PMC6520619   (View Article at PubMed Central)
DOI: DOI:10.1152/jn.00413.2018   (Journal Full-text)

Hyperphagia is common in diabetes and may worsen hyperglycemia and diabetic complications. The responsible mechanisms are not well understood. The hypothalamus is a key center for the control of appetite and energy homeostasis. The ventromedial nucleus (VMH) and arcuate nucleus (ARC) are two critical nuclei involved in these processes. We have reported that R-spondin 1 (Rspo1) and its receptor leucin-rich repeat and G protein-coupled receptor 4 (LGR4) in the VMH and ARC suppressed appetite, but the downstream neuronal pathways are unclear. Here we show that neurons containing cocaine and amphetamine-regulated transcript (CART) in ARC express both LGR4 and insulin receptor; intracerebroventricular injection of Rspo1 induced c-Fos expression in CART neurons of ARC; and silencing CART in ARC attenuated the anorexigenic actions of Rspo1. In diabetic and obese fa/fa rats, Rspo1 mRNA in VMH and CART mRNA in ARC were reduced; this was accompanied by increased food consumption. Insulin treatment restored Rspo1 and CART gene expressions and normalized eating behavior. Chronic intracerebroventricular injection of Rspo1 inhibited food intake and normalized diabetic hyperphagia; intracerebroventricular injection of Rspo1 or insulin increased CART mRNA in ARC. In the CART neuron cell line, Rspo1 and insulin potentiated each other on pERK and β-catenin, and in rats, they acted synergistically to inhibit food intake. Silencing Rspo1 in VMH reduced CART expression in ARC and attenuated the inhibitory effect of insulin on food intake. In conclusion, our data indicated that CART works downstream of Rspo1 and Rspo1 mediated the action of insulin centrally. The altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes. NEW & NOTEWORTHY This study reports that cocaine and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus (ARC) of hypothalamus acted downstream of R-spondin 1 (Rspo1) to inhibit food intake. The Rspo1 mRNA level in ventromedial nucleus (VMH) and CART mRNA level in ARC were reduced in type 1 diabetic rat and obese fa/fa rat. Rspo1 and insulin acted synergistically on phospho-ERK and β-catenin signal pathways and in suppressing food intake. The current results proposed that altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RSPO1Humanobesity  ISORGD:1565558mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 
Rspo1Ratobesity  IEP mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 
Rspo1Mouseobesity  ISORGD:1565558mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 
RSPO1Humantype 1 diabetes mellitus  ISORGD:1565558mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 
Rspo1Rattype 1 diabetes mellitus  IEP mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 
Rspo1Mousetype 1 diabetes mellitus  ISORGD:1565558mRNA:decreased expression:ventromedial nucleus of hypothalamusRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rspo1Ratnegative regulation of eating behavior  IMP  RGD 
CartptRatresponse to insulin  IEP  RGD 
Rspo1Ratresponse to insulin  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cartpt  (CART prepropeptide)
Rspo1  (R-spondin 1)

Genes (Mus musculus)
Rspo1  (R-spondin 1)

Genes (Homo sapiens)
RSPO1  (R-spondin 1)


Additional Information