We tested the hypotheses that steroidogenic factor SF -1 neurons in the hypothalamic ventromedial nucleus VMN provide sexually disparate, endocannabinoid EC - and diet-sensitive glutamatergic input onto proopiomelanocortin POMC neurons.
Electrophysiological recordings were performed in hypothalamic slices from intact and castrated guinea pigs, along with in vitro optogenetic experiments in intact male as well as cycling and ovariectomized female NR5A1-Cre mice.
In slices from castrated male and female guinea pigs, depolarized-induced suppression of excitation DSE time-dependently reduced the amplitude of evoked excitatory postsynaptic currents eEPSCs in POMC neurons generated by electrically stimulating the dorsomedial VMN.
Androgen stimulation rapidly enhanced this DSE, which was also found in insulin-resistant, high-fat diet HFD -fed males. HFD potentiated central cannabinoid-induced hyperphagia in both males and females, but exerted differential influences on cannabinoid-induced increases in energy expenditure.
In NR5A1-Cre mice, the reduction in light-evoked EPSC amplitude caused by postsynaptic depolarization in cycling females was modest in comparison to that seen in intact males. Moreover, the retrograde inhibition of transmission was further accentuated in HFD-fed males. Chemogenetic activation of SF-1 neurons suppressed appetite and increased energy expenditure in males, effects which were attenuated by HFD. Conversely, energy expenditure was increased in estradiol- but not vehicle-treated ovariectomized females.
