Substance P as a novel anti-obesity target

Gastroenterology. 2008 Mar;134(3):747-55. doi: 10.1053/j.gastro.2007.12.032.


Background & aims: Substance P (SP) is an 11-amino acid peptide that belongs to the tachykinin family of peptides. SP acts in the brain and in the periphery as a neuropeptide, neurotransmitter, and hormone affecting diverse physiologic pathways, mainly via its high-affinity neurokinin-1 receptor (NK-1R). Its presence in the hypothalamus and other areas of the brain that regulate feeding as well as in the stomach and small intestine prompted us to investigate its role on appetite control and energy balance.

Methods: CJ 012,255 (CJ), a SP antagonist that binds to NK-1R, was injected into lean, diet-induced obese (DIO), and genetically obese (ob/ob) mice, and its effects on body weight, adiposity, and insulin sensitivity were investigated.

Results: CJ administration prevented weight gain and accumulation of fat after 2 weeks of high-fat feeding, whereas similar CJ treatment in obese mice (following 3 months of high-fat diet) resulted in weight loss, reduction in adiposity, and improvement of insulin sensitivity, in part because of inhibition of food intake. The effects of SP in the control of energy balance are, at least in part, leptin independent because CJ treatment was also effective in leptin-deficient mice. Peripheral SP administration resulted in a mild, dose-dependent increase in food intake, evident 3 hours post-SP injection.

Conclusions: CJ reduces appetite and promotes weight loss in mice. We speculate that NK-1R antagonists, already tested in clinical trials for various diseases, may represent a potential target against obesity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adiposity / drug effects
  • Animals
  • Anti-Obesity Agents / administration & dosage
  • Anti-Obesity Agents / pharmacology*
  • Appetite Regulation / drug effects*
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Dietary Fats / administration & dosage
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Energy Metabolism / drug effects*
  • Feeding Behavior / drug effects*
  • Injections, Intraperitoneal
  • Insulin / blood
  • Leptin / deficiency
  • Leptin / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Neurokinin-1 Receptor Antagonists*
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / physiopathology
  • Receptors, Neurokinin-1 / metabolism
  • Substance P / metabolism*
  • Time Factors


  • 6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid
  • Anti-Obesity Agents
  • Blood Glucose
  • Bridged Bicyclo Compounds, Heterocyclic
  • Dietary Fats
  • Insulin
  • Leptin
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Substance P