Circadian-timed dopamine agonist treatment reverses high-fat diet-induced diabetogenic shift in ventromedial hypothalamic glucose sensing

Abstract

Introduction: Within the ventromedial hypothalamus (VMH), glucose inhibitory (GI) neurons sense hypoglycaemia while glucose excitatory (GE) neurons sense hyperglycaemia to initiate counter control mechanisms under normal conditions. However, potential electrophysiological alterations of these two neuronal types in vivo in insulin-resistant states have never been simultaneously fully documented. Further, the anti-diabetic effect of dopamine agonism on this VMH system under insulin resistance has not been studied. Methods: This study examined the impact of a high-fat diet (HFD) on in vivo electrophysiological recordings from VMH GE and GI neurons and the ability of circadian-timed dopamine agonist therapy to reverse any adverse effect of the HFD on such VMH activities and peripheral glucose metabolism. Results: HFD significantly inhibited VMH GE neuronal electrophysiological response to local hyperglycaemia (36.3%) and augmented GI neuronal excitation response to local hypoglycaemia (47.0%). Bromocriptine (dopamine agonist) administration at onset of daily activity (but not during the daily sleep phase) completely reversed both VMH GE and GI neuronal aberrations induced by HFD. Such timed treatment also normalized glucose intolerance and insulin resistance. These VMH and peripheral glucose metabolism effects of circadian-timed bromocriptine may involve its known effect to reduce elevated VMH noradrenergic activity in insulin-resistant states as local VMH administration of norepinephrine was observed to significantly inhibit VMH GE neuronal sensing of local hyperglycaemia in insulin-sensitive animals on regular chow diet (52.4%). Conclusions: HFD alters VMH glucose sensing in a manner that potentiates hyperglycaemia and this effect on the VMH can be reversed by appropriately circadian-timed dopamine agonist administration.