Peripheral Endocannabinoid Control of Feeding Behavior and Obesity
- Author(s): Argueta, Donovan Alexander
- Advisor(s): DiPatrizio, Nicholas V
- et al.
The endocannabinoid (eCB) system is a key modulator of central brain processes that control feeding, however recent evidence points to peripheral mechanisms by which eCB signaling may modulate feeding in various disease states. This body of work provides novel mass spectrometric analyses for components of the eCB system, while describing the pitfalls of currently used techniques. Using the described methods, a role for increased small intestinal eCB ligands signaling via peripheral cannabinoid type 1 receptor (CB1R) in the control of hyperphagia is discussed in the context of obesity. These findings were enhanced by further scrutiny of the intestinal eCB system, which revealed that corn-oil induced secretion of an intestine-derived satiation peptide, cholecystokinin (CCK), is blunted by CB1R activation; activation occurred via pharmacological agonists or enhanced eCB levels following diet induced obesity. Further, administration of a CCKA receptor antagonist, devazepide, blocked the anorexigenic effects of peripheral CB1R restriction, suggesting that peripheral CB1R act via intestine derived CCK to block satiation by impaired gut-brain signaling. Additionally, helminth infection was used to evaluate intestinal and lung eCB levels in a model of hookworm infection. For the first time, it was observed that the helminth Nippostrongylus brasiliensis produces endocannabinoids. Together, this body of work provides novel insight to the varied roles that intestinal and peripheral eCBs have during obesity in the modulation of feeding behaviors and immune responses.