Abstract
The endocannabinoid (eCB) system regulates energy homeostasis and is linked to obesity development. However, the exact dynamic and regulation of eCBs in the hypothalamus during obesity progression remain incompletely described and understood. Our study examined the time course of responses in two hypothalamic eCBs, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamine (AEA), in male and female mice during diet-induced obesity and explored the association of eCB levels with changes in brown adipose tissue (BAT) thermogenesis and body weight. We fed mice a high-fat diet (HFD), which induced a transient increase (substantial at 7 days) in hypothalamic eCBs, followed by a progressive decrease to basal levels with a long-term HFD. This transient rise at early stages of obesity is considered a physiologic compensatory response to BAT thermogenesis, which is activated by diet surplus. The eCB dynamic was sexually dimorphic: hypothalamic eCBs levels were higher in female mice, who became obese at later time points than males. The hypothalamic eCBs time course positively correlated with thermogenesis activation, but negatively matched body weight, leptinemia, and circulating eCB levels. Increased expression of eCB-synthetizing enzymes accompanied the transient hypothalamic eCB elevation. Icv injection of eCB did not promote BAT thermogenesis; however, administration of thermogenic molecules, such as central leptin or a peripheral β3-adrenoreceptor agonist, induced a significant increase in hypothalamic eCBs, suggesting a directional link from BAT thermogenesis to hypothalamic eCBs. This study contributes to the understanding of hypothalamic regulation of obesity.
Highlights
The endocannabinoid system regulates energy homeostasis and is linked to obesity development
A significant increase in body weight gain was not appreciated until 60 days of administration of an high-fat diet (HFD) compared with an standard diet (SD) (Fig. 1A, supplemental Fig. S1)
In line with these results, plasmatic levels of leptin were significantly increased in male mice after 28 days of HFD feeding compared with control diet, whereas female mice did not show hyperleptinemia until 60 days of HFD administration, and leptin levels were considerably lower at this point than those observed in male mice (Fig. 1B)
Summary
The endocannabinoid (eCB) system regulates energy homeostasis and is linked to obesity development. 2-AG levels are increased in different genetic models of obesity: Zucker rats, db/db mice, or ob/ob mice [9] In line with these evidences, specific deletion of the main eCB receptor (CB1) in the hypothalamus resulted in increased energy expenditure and brown adipose tissue (BAT) thermogenesis, leading to a reduction in body weight, while food intake remained unchanged [10]. These studies, together with others on genetic animal models [11,12,13], suggest that the activation of the eCB system in the hypothalamus leads to reduced energy expenditure and promotes obesity [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
