Article

Hypothalamic CB1 Cannabinoid Receptors Regulate Energy Balance in Mice

Group Energy Balance and Obesity, Institut National de la Santé et de la Recherche Médicale, Unité 862, Neurocentre Magendie, 146 Rue Léo Saignat, F-33077 Bordeaux, France.
Endocrinology (Impact Factor: 4.5). 07/2012; 153(9):4136-43. DOI: 10.1210/en.2012-1405
Source: PubMed

ABSTRACT

Cannabinoid type 1 (CB(1)) receptor activation is generally considered a powerful orexigenic signal and inhibition of the endocannabinoid system is beneficial for the treatment of obesity and related metabolic diseases. The hypothalamus plays a critical role in regulating energy balance by modulating both food intake and energy expenditure. Although CB(1) receptor signaling has been implicated in the modulation of both these mechanisms, a complete understanding of its role in the hypothalamus is still lacking. Here we combined a genetic approach with the use of adeno-associated viral vectors to delete the CB(1) receptor gene in the adult mouse hypothalamus and assessed the impact of such manipulation on the regulation of energy balance. Viral-mediated deletion of the CB(1) receptor gene in the hypothalamus led to the generation of Hyp-CB(1)-KO mice, which displayed an approximately 60% decrease in hypothalamic CB(1) receptor mRNA levels. Hyp-CB(1)-KO mice maintained on a normocaloric, standard diet showed decreased body weight gain over time, which was associated with increased energy expenditure and elevated β(3)-adrenergic receptor and uncoupling protein-1 mRNA levels in the brown adipose tissue but, surprisingly, not to changes in food intake. Additionally, Hyp-CB(1)-KO mice were insensitive to the anorectic action of the hormone leptin (5 mg/kg) and displayed a time-dependent hypophagic response to the CB(1) inverse agonist rimonabant (3 mg/kg). Altogether these findings suggest that hypothalamic CB(1) receptor signaling is a key determinant of energy expenditure under basal conditions and reveal its specific role in conveying the effects of leptin and pharmacological CB1 receptor antagonism on food intake.

0 Followers
 · 
10 Reads
    • "Interestingly, hypothalamic CB1 knockdown by 60% has no effects on basal food consumption, although the animals are less responsive to the hypophagic activity of the CB1 inverse BioFactors agonist rimonabant, and become insensitive to the anorexigenic actions of leptin [9], thus strengthening the physiological link between leptin and the ECS in the brain. This link was first shown in the pioneering study of Di Marzo et al., [18], who reported that intravenous leptin injection in rats decreases both AEA and 2-AG hypothalamic levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). These alterations result in: i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the RVM, as assessed by patch clamp and in vivo electrophysiology; ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross-talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signalling.Neuropsychopharmacology accepted article preview online, 17 June 2015. doi:10.1038/npp.2015.173.
    No preview · Article · Jun 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
  • Source
    • "locomotor activity and gas exchange analysis were carried out in calorimetric chambers (TSE systems, Bad Homburg, Germany) after 72 h of acclimatization, as previously described in Ref. [22]. VO 2 values reported in figures were expressed per animal. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic flexibility allows rapid adaptation to dietary change, however little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.Figure optionsDownload full-size imageDownload as PowerPoint slide
    Full-text · Article · Aug 2014 · Molecular Metabolism
    • "Interestingly, hypothalamic CB1 knockdown by 60% has no effects on basal food consumption, although the animals are less responsive to the hypophagic activity of the CB1 inverse BioFactors agonist rimonabant, and become insensitive to the anorexigenic actions of leptin [9], thus strengthening the physiological link between leptin and the ECS in the brain. This link was first shown in the pioneering study of Di Marzo et al., [18], who reported that intravenous leptin injection in rats decreases both AEA and 2-AG hypothalamic levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endocannabinoid system (ECS) is a widespread intercellular signaling system that plays a critical role in energy homeostasis, meant as the precise matching of caloric intake with energy expenditure which normally keeps body weight stable over time. Complex interactions between environmental and neurohormonal systems directly contribute to the balance of energy homeostasis. This review highlights established and more recent data on the brain circuits in which the ECS plays an important regulatory role, with focus on the hypothalamus, a region where numerous interacting systems regulating feeding, satiety, stress, and other motivational states coexist. Although not meant as an exhaustive review of the field, this article will discuss how endocannabinoid tone, in addition to reinforcing reward circuitries and modulating food intake and the salience of food, controls lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in the skeletal muscle and pancreas are also emerging and are briefly discussed. This review provides new perspectives into endocannabinoid control of the neurochemical causes and consequences of energy homeostasis imbalance, a knowledge that might lead to new potential treatments for obesity and related morbidities. © 2014 BioFactors, 2014.
    No preview · Article · Jul 2014 · BioFactors
Show more