Central Inhibition of HDAC6 Re-Sensitizes Leptin Signaling During Obesity to Induce Profound Weight Loss

Leptin resistance during excess weigh gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of Leptin receptor b (LepR) signaling during obesity is still elusive. Here we report that histone deactylase 6 (HDAC6) interacts with LepR, reducing the latter’s activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of obese mice with blood brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to a potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in AgRP-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors result in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally-, but not peripherally-acting HDAC6 inhibitors as potent leptin-sensitizers and anti-obesity agents. To investigate the leptin sensitizer celastrol-regulated orexigenic or anorexigenic genes in the hypothalamus, we decided that a pair-fed control should be included, in which the food intake of pair-fed mice match those treated with celastrol, along with satiated control mice, when analyzing celastrol-treated mice to identify the genes involved in leptin resistance. DIO mice were acclimated with DMSO with daily i.p. injections for 1 week and then randomly divided into 4 groups for a subsequent 4-day treatment. 1) Vehicle (Veh), treated with DMSO and ad libitum access to food, 2) CS, treated with Celastrol (100μg/kg/day, i.p.) and ad libitum access to food, 3) PF, pair-fed to Celastrol-treated group, in which 0.5g high fat diet per mice per day was given (0.34g for dark cycle and 0.16g for light cycle) (a little bit less than 0.8g, the average amount of diet Celastrol-treated mice consumed), 4) PF/CS, treated with Celastrol and given the same amount of food and at the same intervals as the PF group. On the fourth day around 8:00 am, all mice received a final injection and 6 hours later blood glucose (mg/dl) levels were measured before tissue collection.