between tasting emulsions contained mineral oil alone or
those also containing linoleic acid, rats exhibited strong preferences for linoleic acid. Notably, pharmacological blockade of peripheral CB1Rs inhibited preference for linoleic acid.
Collectively, these studies reveal that tasting specific unsaturated dietary fats drives endocannabinoid signaling in the small
intestine of rats, and this signaling at local CB1Rs controls preferences for foods containing linoleic acid.
PATHWAYS FOR THERAPEUTIC GAIN
In summary, we propose that gut-brain endocannabinoid
signaling serves a critical role in promoting the intake of
energy-rich foods for survival. Overactive gut-brain endocannabinoid activity, however, may promote overeating of energy-rich foods and contribute to obesity, type- 2 diabetes, and
Pharmacological inhibitors of CB1Rs show clinical promise
for the treatment of obesity and related metabolic disorders.
Unfortunately, CB1R antagonists that cross into the brain lead
to serious psychiatric side effects (e.g., depression).
Recent studies discussed above from our group and others suggest that targeting CB1Rs in peripheral organs with specially designed CB1R inhibitors that do not reach the brain also
reduces feeding and body weight similarly to inhibitors that do
reach the brain. Thus, targeting peripheral CB1Rs for therapeutic
gain is attractive due to reduced risks of side effects when compared to brain-penetrant cannabinoid receptor ligands. Further
development and design of peripherally-restricted CB1R ligands
will be instrumental for the safe treatment of metabolic syndrome and possibly eating disorders (e.g., binge eating disorder).
Nicholas DiPatrizio’s passion for scientific discovery was solidified during his undergraduate research studies at Temple University in
Philadelphia, USA, where he studied the role
for cannabinoid signaling pathways in feeding
behaviors. He subsequently earned a Biomedical
Ph.D. in the Neurosciences at Drexel University
College of Medicine, and completed his postdoctoral fellowship in the laboratory of the lipid biochemist,
Daniele Piomelli, at the University of California Irvine School of
Medicine. DiPatrizio is a recipient of the National Institutes of
Health Pathway to Independence K99/R00 grant award from the
National Institute on Drug Abuse for his work examining the role
for endocannabinoids in mediating dietary fat intake. In 2015,
he launched his independent research program as an assistant
professor of biomedical sciences at the University of California’s
newest medical school located in Riverside, California, USA. His
research program investigates the neural and molecular mechanisms that regulate sensory processing, food reward, and energy
balance in health and disease.
1. DiPatrizio, N.V. and Piomelli, D. (2015) “Intestinal lipid-derived signals that sense dietary fat.” J. Clin. Invest. 125:
2. Running C.A., Craig, B.A., and Mattes, R.D. (2015)
“Oleogustus: The unique taste of fat.” Chem. Senses 40:
3. DiPatrizio, N.V. (2014) “Is fat taste ready for
primetime?” Physiol. Behav. 136: 145–154.
4. DiPatrizio, N.V., Astarita, G., Schwartz, G., Li. X., and
Piomelli, D. (2011) “Endocannabinoid signal in the gut
controls dietary fat intake.” Proc. Natl. Acad. Sci. USA
5. DiPatrizio, N.V., Joslin, A., Jung, K.M., and Piomelli, D.,
(2013) “Endocannabinoid signaling in the gut mediates
preference for dietary unsaturated fats.” Faseb J 27:
FIG. 2. Tasting dietary fats drives gut-brain endocannabinoid signaling and further feeding. Fatty foods ( 1) enter the mouth where
their triglyceride content is hydrolyzed by lipases, and free fatty
acids are released. Free fatty acids are detected by receptors
located in the oral cavity ( 2), which in turn, activate nerves that
carry electrical signals to the brain for processing. The brain communicates bi-directionally with peripheral organs via the vagus
nerve. Recent evidence suggests that the presence of fats in the
oral cavity increases neurotransmission carried by the vagus
nerve to the gut ( 3) and stimulates an upregulation of endocannabinoid levels in small intestinal epithelium of rodents ( 4).
Endocannabinoid signaling at local cannabinoid CB1Rs is thought
to modify vagal signaling back to the brain ( 5) and promote the
further consumption of fatty foods ( 6).