Hypothalamic endocannabinoids inversely correlate with the development of diet-induced obesity in male and female mice

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 male. 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. Intracerebroventricular 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.We thank Dr. Gemma Fabriàs and Alexandre García from the Research Unit of BioActive Molecules (Institut de Química Avançada de Catalunya, IQAC) for their technical assistance in the analysis of eCB levels. This work was supported by the Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Downloaded from www.jlr.org by guest, on June 3, 2019 Desarrollo Regional (FEDER) (Grants SAF2014-52223-C2-2-R to NC, SAF2017-83813-C3-3-R to NC and RR-R, SAF2017-83813-C3-1-R to DS and LH), the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 to DS), the Generalitat de Catalunya (2014SGR465 to DS and NC; 2017SGR152 to JC), Fundació La Marató de TV3 (Grant 87/C/2016 to DS and NC). AF is the recipient of a fellowship from the Agència de Gestió d’Ajuts Universitaris i de la Recerca (AGAUR) in Catalonia.Peer reviewe