Energy metabolism and hindbrain AMPK: regulation by estradiol

Abstract

Nerve cell energy status is screened within multiple classically defined hypothalamic and hindbrain components of the energy balance control network, including the hindbrain dorsal vagal complex (DVC). Signals of caudal DVC origin have a physiological role in glucostasis, e.g., maintenance of optimal supply of the critical substrate fuel, glucose, through control of motor functions such as fuel consumption and gluco-counterregulatory hormone secretion. A2 noradrenergic neurons are a likely source of these signals as combinatory laser microdissection/high-sensitivity Western blotting reveals expression of multiple biomarkers for metabolic sensing, including adenosine 5'-monophosphate-activated protein kinase (AMPK). Hypoglycemia elicits estradiol-dependent sex differences in A2 AMPK activation as phospho-AMPK (pAMPK) expression is augmented in male and ovariectomized (OVX) female, but not estrogen-replaced, OVX rats. This dichotomy may reflect, in part, estradiol-mediated up-regulation of glycolytic and tricarboxylic acid cycle enzyme expression during hypoglycemia. Our new model for short-term feeding abstinence has physiological relevance to planned (dieting) or unplanned (meal delay) interruption of consumption in modern life, which is negatively correlated with appetite control and obesity, and is useful for investigating how estrogen may mitigate the effects of disrupted fuel acquisition on energy balance via actions within the DVC. Estradiol reduces DVC AMPK activity after local delivery of the AMP mimic, 5-aminoimidazole-4-carboxamide-riboside, or cessation of feeding for 12 h but elevates pAMPK expression when these treatments are combined. These data suggest that estrogen maintains cellular energy stability over periods of suspended fuel acquisition and yet optimizes, by DVC AMPK-dependent mechanisms, counter-regulatory responses to metabolic challenges that occur during short-span feeding abstinence.

Central regulation of energy metabolism by estrogens

“…Current evidence has shown that estradiol controls hypothalamic astrocyte AMPK and hindbrain catecholamine-dependent activation of this cell-specific sensor by hypoglycemia [106] . In keeping with this evidence, recent data have also proposed that 17β-estradiol acting on AMPK in the hindbrain dorsal vagal complex (DVC) might be also involved in the induction of counterregulatory responses [107] . Although these data are of relevance, further work involving genetic models will be necessary to address the physiological relevance of estrogen on AMPK-induced effects on glucose homeostasis.…”

The Role of Sirt1 in Ischemic Stroke: Pathogenesis and Therapeutic Strategies

“…AMP-activated protein kinase (AMPK) is considered to be a major metabolic energy sensor. Decreased cellular energy charge (increased AMP/ATP ratio) activates AMPK and then regulates energy metabolic homeostasis ( Briski et al, 2014 ; Zainal Abidin et al, 2015 ). Pharmacologic inhibition of AMPK was reported to alleviate ischemic damage in an ischemia model ( Li et al, 2007 ).…”

Response of catecholaminergic neurons in the mouse hindbrain to glucoprivic stimuli is astrocyte dependent

“…Hindbrain catecholaminergic (CA) neurons are critically involved in glucoregulatory functions. Selective immunotoxin lesions, gene silencing, chemogenetic activation, and localized glucoprivation have revealed that activation of these neurons is necessary for elicitation of feeding, corticosterone secretion, and elevation of adrenal medullary secretion in response to glucose deficit ( 7 , 33 , 34 , 59 , 62 ). Additionally, CA NST neurons may be involved in producing the increased gastric motility evoked by glucose deficit ( 29 , 66 , 67 ).…”