Abstract
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. By contrast, retrograde signaling at VMN/ARC POMC synapses was markedly attenuated in periovulatory females. 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. Estradiol attenuated the DSE in light-evoked EPSC amplitude in slices from ovariectomized females. 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. Together with our previous studies indicating that DSE in POMC neurons is EC-mediated, these findings indicate that VMN SF-1/ARC POMC synapses represent a sexually differentiated, EC- and diet-sensitive anorexigenic component within the hypothalamic energy balance circuitry.
Highlights
Energy balance is regulated through interactions between the gastrointestinal tract (GI), brainstem and the hypothalamus
Previous studies have demonstrated that cannabinoid-induced changes in energy intake and core body temperature are sexually differentiated (Diaz et al, 2009), and elevated EC tone and signaling are implicated in diet-induced obesity/insulin resistance (Kim et al, 2013)
The results from the present study demonstrate that steroidogenic factor (SF)-1 neurons provide a source of sexually disparate, EC-sensitive glutamatergic input onto POMC neurons that account, at least in part, for sex and dietary differences in the cannabinoid regulation for energy homeostasis
Summary
Energy balance is regulated through interactions between the gastrointestinal tract (GI), brainstem and the hypothalamus. Rodents and humans lacking leptin or a functional leptin receptor are immensely obese and hyperglycemic (Chua et al, 1996; Clément et al, 1998; Belgardt et al, 2009), while mice lacking the insulin receptor display a more mild obese phenotype (Brüning et al, 2000) Both leptin and insulin will depolarize POMC neurons via activation of transient receptor potential (TRP)C5 channels, which occurs through insulin and leptin receptor-mediated activation of phosphatidylinositol-3-kinase (PI3K) and leads to increased firing of POMC neurons (Cowley et al, 2003; Qiu et al, 2010, 2014). Leptin and insulin modulate POMC neuronal firing by presynaptic action on neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons, which will inhibit the release of gamma-amino butyric acid (GABA) from terminals impinging onto POMC neurons (Vong et al, 2011)
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