Leptin-regulated endocannabinoids are involved in maintaining food intake

Abstract

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.

Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward

“…Microinjections of the endocannabinoid 2-AG directly into the medial shell of nucleus accumbens similarly increases food intake in rats (Kirkham et al, 2002). Conversely, food-related manipulations, such as deprivation and satiety, or access to a palatable diet produce changes in CB1 receptor density and in dialysate levels of endogenous anandamide and 2-AG in nucleus accumbens and other brain areas, and modulate appetite stimulation by cannabinoids (Di Marzo et al, 2001;Harrold et al, 2002;Kirkham et al, 2002). Most relevant to this study, systemic administration of D 9 -THC in rats is reported to cause eventual increase in affective orofacial 'liking' reactions elicited by the taste of sucrose, suggesting enhancement of taste palatability (Jarrett et al, 2005).…”

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

“…These compounds, also called endocannabinoids, activate cannabinoid receptors CB1 and CB2. Activation of these receptors has been reported to induce several biological effects [4,5] such as relief of pain [6] and anxiety [7], increase of appetite [8] and reduction of intraocular pressure [9]. Additionally, the activation of CB2 receptors is involved in the dampening of inflammation, lowering of blood pressure, and suppression of peripheral pain [10].…”

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

“…This endogenous system has been implicated in several physiological functions including the modulation of pain (Calignano et al, 1998;Richardson et al, 1998;Walker et al, 1999), feeding (Di Marzo et al, 2001), drug dependence (Ledent et al, 1999;Lichtman et al, 2001;Gonzalez et al, 2002), excitotoxicity (Marsicano et al, 2003), anxiety (Kathuria et al, 2003), depression (Gobbi et al, 2005;Witkin et al, 2005), and cognition (Terranova et al, 1996;Marsicano et al, 2002;Varvel et al, 2005a). Of particular interest has been the discovery of fatty-acid amide hydrolase (FAAH), an integral membrane enzyme that is primarily responsible for the degradation of the endocannabinoid anandamide as well as several non-cannabinoid fatty-acid amides (FAAs; (Cravatt et al, 1996)).…”