Abstract
It is unclear if habituation of hindbrain A2 metabolo‑sensory neurons to recurrent insulin-induced hypoglycemia (RIIH) correlates with estradiol-dependent adjustments in energy metabolism that favor positive energy balance. Laser-microdissected A2 cells from estradiolor oil-implanted ovariectomized female rats were analyzed by Western blot to assess effects of three prior daily insulin injections on basal and hypoglycemic patterns of catecholamine biosynthetic enzyme dopamine-beta-hydroxylase (DβH) and rate-limiting energy pathway enzyme protein expression. Precedent hypoglycemia respectively decreased or increased baseline DβH expression in estradiol- (E) vs. oil (O)-treated rats; this protein profile was further suppressed or augmented in those animals at 2 hr after re-induction of hypoglycemia. These data suggest that estradiol may curtail A2 noradrenergic‑controlled functions both in the midst of and between hypoglycemic bouts. Results also show that prior hypoglycemia exposure upregulated A2 neuron glycolytic enzyme protein levels when E was present, and exerted differential effects on basal and hypoglycemia-associated respiratory chain and fatty acid synthetic pathway enzyme expression. E may thus accordingly amplify glycolysis-derived metabolites/energy, coupled with reduced reliance on oxidative phosphorylation, and activate the fatty acid synthetic pathway during RIIH. E may also be of benefit by preventing maladaptive reductions in A2 neuron Krebs cycle/electron transport enzyme expression during re-exposure to hypoglycemia. Augmentation of negative energy balance during this recurring metabolic stress in the absence of E is a likely impetus for augmented vs. decreased A2 signaling of energy imbalance by DβH in O vs. E rats during RIIH.
Highlights
Hindbrain noradrenergic neurons, including the A2 cell group located in the caudal dorsal vagal complex, are involved in neural regulation of a wide array of physiological, behavioral and cognitive functions that maintain homeostasis, including control of emotional, endocrine, and autonomic responses to stress (Rinaman 2011)
Sc E‐filled capsule implantation resulted in plasma hormone concentrations of 21.4+0.3 (E‐V4), 21.9+0.4 (E‐I3V), and 21.7+0.4 (E‐I4) pg/mL; circulating estradiol was undetectable in groups of OVX+oil rats
Blood glucose concentrations were measured with an AccuCheck Advantage glucometer (Roche diagnostics, Indianapolis, IN), as described (Kale et al 2006)
Summary
Hindbrain noradrenergic neurons, including the A2 cell group located in the caudal dorsal vagal complex (cDVC), are involved in neural regulation of a wide array of physiological, behavioral and cognitive functions that maintain homeostasis, including control of emotional, endocrine, and autonomic responses to stress (Rinaman 2011). A2 noradrenergic neurons are implicated in metabolo‐sensory function by characteristic biomarker expression, including glucokinase (Briski et al 2009), the ATP‐dependent potassium channel, KATP (Briski et al 2009), and the ultra‐sensitive energy gauge adenosine 5’‐monophosphate‐activated protein kinase (AMPK) (Cherian and Briski 2011, 2012). Evidence for glucose antimetabolite‐induced increases in Fos protein (Briski and Marshall 2000) and dopamine‐β‐hydroxylase (DβH) mRNA (Li et al 2006) expression by A2 neurons provides proof of functional susceptibility to glucoprivation. A2 cells communicate hypoglycemia‐associated cell energy imbalance to the brain gluco‐regulatory network as insulin‐induced hypoglycemia‐associated patterns of hypothalamic metabolo‐sensory neuron AMPK activation, hypothalamic metabolic effector transmitter expression, and hypoglycemic hyperphagia are normalized by substrate fuel repletion of the cDVC (Gujar et al 2014). Evidence that hypoglycemia‐induced transcriptional activation in the male rat DVC is diminished by precedent exposure (Paranjape and Briski 2005) prompts speculation that metabolo‐sensory function in that site may be vulnerable to maladaptive desensitization to hypoglycemia (Smith and Amiel 2002)
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