Cellular & Integrative Physiology Seminar - Ken Mackie, MD

Ken Mackie, MD
Distinguished Professor
Dept of Psychological and Brain Sciences
Jack and Linda Gill Chair, Gill Center for Biomolecular Science
Indiana University Bloomington

Title: "Cannabinoids for weight loss:  A twisted tale."

Summary: Human use of cannabis is well known to stimulate the consumption of calorically dense, nutritionally poor food (AKA “the munchies”).  Similarly, in preclinical studies, both exogenous and endogenous cannabinoids stimulate the consumption of highly palatable, calorically dense food.  Thus, it is surprising that a substantial majority of epidemiological studies have found that chronic cannabis use is associated with reductions in weight, central obesity, risk for metabolic syndrome and type II diabetes, and inflammatory markers, despite higher caloric intake in cannabis users.  

To understand the metabolically protective effects of cannabis, we have investigated THC’s interactions with GPR119, a nutrient-sensing G protein coupled receptor, found on pancreatic beta cells and gut enteroendocrine K and L cells. Its activation increases insulin secretion and sensitivity, preserves of beta cell mass, and stimulates incretin secretion.  We found that THC and its metabolites activate GPR119 and increase incretin secretion.  

Turning to in vivo studies, we found that two weeks of THC administration (oral or i.p.) decreased weight in diet-induced obese (DIO) mice in a dose-dependent fashion.  THC also improved glucose tolerance in these mice.  In contrast, the same THC treatment in DIO GPR119 mice failed to significantly decrease weight.  THC also decreased weight gain in adolescent mice simultaneously fed a high-fat diet and oral THC. These results suggest that the surprising metabolic health of chronic cannabis users may be in part a consequence of GPR119 activation by THC and its metabolites.