Cannabinoids, both endogenous and exogenous, exert a profound impact on the hypothalamic control of biological processes such as reproduction and energy homeostasis. The overall goal of this proposal is to gain a better understanding of the cannabinoid regulation of energy homeostasis, and the cellular mechanism(s) by which they affect the excitability of anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus to alter these actions. The fundamental hypothesis is that endocannabinoids modulate energy balance in a sex- and diet-dependent fashion that can be differentially influenced by gonadal steroid hormones. They do so, in large part, via retrograde inhibition of excitatory glutamatergic neurotransmission in POMC neurons in a manner that is sexually differentiated, and dependent on dietary composition and the gonadal steroid milieu. Endocannabinoid regulation of energy homeostasis and synaptic transmission onto POMC neurons will be studied using a transgenic, Nr5a1-cre animal model, in which either channelrhodpsin-2 or a modified Gq-coupled muscarinic M3 receptor is delivered via a viral vector construct into the hypothalamic ventromedial nucleus (VMN) and integrated into neurons expressing steroidogenic factor- 1 (SF-1; encoded by the Nr5a1 gene) for in vivo and in vitro optogenetic experimentation. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively, and treated with estradiol, testosterone, or their respective vehicles according to well-established protocols.
In Specific Aim 1, I will evaluate the mechanisms through which long-term exposure to a Westernized high-fat diet differentially enhances endocannabinoid sensitivity in males and females by assessing how it influences the capability of endogenous cannabinoids to retrogradely inhibit light- and chemically- evoked glutamatergic neurotransmission at VMN SF-1/ARC POMC synapses.
In Specific Aim 2, the objective is to determine whether these high-fat diet-induced alterations in endocannabinoid sensitivity effectively translate into changes in energy balance. Specifically, I will evaluate whether high-fat diet exposure differentially attenuates the capability of opto- and chemogenetically stimulated VMN SF-1 neurons to suppress energy intake and enhance energy expenditure, and whether these adaptations are due to alterations in the expression/activity of the energy-sensing signaling molecules like phosphatidylinositol-3-kinase and AMP-activated protein kinase. This proposal describes an integrated approach to study sex differences in, and gonadal steroid hormonal influences on, the cannabinoid regulation of energy balance. Further, it will elucidate the relevant cellular mechanisms and neuroanatomical substrates that differentially predispose males and females to dysregulated endocannabinoid signaling and food consumption under conditions of diet-induced obesity/insulin resistance.

Public Health Relevance

When talking about sex differences in the cannabinoid regulation of energy balance, we mean that there are differences between males and females in their sensitivity to cannabinoid- induced changes in energy intake and expenditure. This project is right in line with one of the major goals of NIDA, which is to promote the conduct of research on sex/gender differences and women's health relating to drugs of abuse. The findings generated from this research will advance our understanding of exactly how cannabinoid intoxication increases appetite and alters metabolism more effectively in males than in females, and under different dietary conditions. They also will heighten our awareness that the therapeutic effectiveness of cannabinoids in treating cancer- and AIDS-related body wasting, as well as obesity and food addiction, may differ between men and women, which will necessitate the development of gender-specific strategies for improving these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15DA024314-03
Application #
9302013
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (86)A)
Program Officer
Su, Shelley
Project Start
2008-08-01
Project End
2020-02-29
Budget Start
2017-04-01
Budget End
2020-02-29
Support Year
3
Fiscal Year
2017
Total Cost
$401,082
Indirect Cost
$107,621
Name
Western University of Health Sciences
Department
Other Basic Sciences
Type
Schools of Osteopathic Medicine
DUNS #
093373694
City
Pomona
State
CA
Country
United States
Zip Code
91766
Qiu, Jian; Bosch, Martha A; Meza, Cecilia et al. (2018) Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance. Endocrinology 159:647-664
Qiu, J; Wagner, E J; Rønnekleiv, O K et al. (2018) Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. J Neuroendocrinol 30:
Conde, Kristie; Fabelo, Carolina; Krause, William C et al. (2017) Testosterone Rapidly Augments Retrograde Endocannabinoid Signaling in Proopiomelanocortin Neurons to Suppress Glutamatergic Input from Steroidogenic Factor 1 Neurons via Upregulation of Diacylglycerol Lipase-?. Neuroendocrinology 105:341-356
Wagner, Edward J (2016) Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis. Front Neuroendocrinol 40:101-9
Conde, Kristie; Meza, Cecilia; Kelly, Martin J et al. (2016) Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via Gq-Coupled, Membrane-Initiated Signaling. Neuroendocrinology 103:787-805
Mela, Virginia; Vargas, Amanda; Meza, Cecilia et al. (2016) Modulatory influences of estradiol and other anorexigenic hormones on metabotropic, Gi/o-coupled receptor function in the hypothalamic control of energy homeostasis. J Steroid Biochem Mol Biol 160:15-26
Borgquist, Amanda; Meza, Cecilia; Wagner, Edward J (2015) Role of neuronal nitric oxide synthase in the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. J Neurophysiol 113:904-14
Borgquist, Amanda; Meza, Cecilia; Wagner, Edward J (2015) The role of AMP-activated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis. Am J Physiol Endocrinol Metab 308:E482-95
Borgquist, A; Rivas, V M; Kachani, M et al. (2014) Gonadal steroids differentially modulate the actions of orphanin FQ/nociceptin at a physiologically relevant circuit controlling female sexual receptivity. J Neuroendocrinol 26:329-40
Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda et al. (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682-93

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