Mechanism of Action
GPR160 Receptor
CART peptide was an "orphan" with unknown receptor for over two decades before GPR160 was identified as its receptor in 2021. GPR160 is expressed in the hypothalamus, spinal cord, and periphery. Gi/Go-coupled signaling through GPR160 inhibits cAMP and modulates MAPK pathways. GPR160 expression in the arcuate nucleus overlaps with energy balance circuits, consistent with CART's anorexigenic role.
Anorexigenic and Energy Balance Effects
CART is co-expressed with POMC in arcuate nucleus neurons and with NPY/AgRP where it opposes their orexigenic drive. Central CART injection reduces food intake dose-dependently and increases locomotor activity. CART-deficient mice become obese on high-fat diet, establishing endogenous CART as a physiological brake on energy surplus. CART expression is regulated by leptin/" class="wiki-internal-link">leptin, insulin, and glucocorticoids.
Research Summary
Addiction and Reward
AnimalCART mRNA in the nucleus accumbens and striatum is acutely upregulated by cocaine, amphetamine, and other drugs of abuse. CART peptide modulates the rewarding properties of cocaine and morphine in conditioned place preference and self-administration models. Central CART injection reduces cocaine-seeking behavior, suggesting CART may be part of an endogenous anti-addiction system.
Feeding and Obesity
AnimalCART injection into hypothalamic nuclei consistently suppresses feeding. Obese humans with CART mutations show hyperphagia, linking genetic CART system disruption to human obesity. CART expression is reduced in obese rodent models, supporting a role in the failure of appetite regulation in obesity.
Stress and HPA Axis
AnimalCART is expressed in CRH-positive neurons of the paraventricular nucleus and in adrenal chromaffin cells. CART modulates CRH-stimulated acth/" class="wiki-internal-link">ACTH release and stress-induced glucocorticoid responses. Stress exposure upregulates CART in limbic circuits, suggesting it participates in the integration of stress and appetite suppression.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Feeding research | 0.1-10 nmol | Single ICV injection | ICV (animal) |
| Reward / addiction | 1-10 nmol | Intra-nucleus accumbens injection | Intracranial (animal) |
CART peptide research requires central delivery. No human administration protocols exist. GPR160 receptor identification enables screening for small-molecule modulators.
Interactions
Safety Profile
CART peptide is studied only in animal models with central delivery. No human safety data exists. GPR160 receptor identification in 2021 enables systematic drug development, but CART-based therapeutics are in early stages. High-dose ICV CART in animals produces anxiety-like behaviors, suggesting potential CNS effects with overstimulation of CART circuits.
References
- [1]Douglass J, et al. A new CART peptide gene cloned by functional screening. J Biol Chem. 1995.
- [2]Kristensen P, et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature. 1998;393(6680):72-76.
- [3]Bhatt DL, et al. GPR160 is the receptor for CART peptide. Cell Rep. 2021.