Leucine Deprivation Stimulates Fat Loss via Increasing CRH Expression in the Hypothalamus and Activating The Sympathetic Nervous System

Abstract

We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three β-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.

Branched chain amino acids and metabolic regulation

“…In contrast, our research work indicated that leucine deprivation for 7 d resulted in a 15% reduction in food intake and body weight and an approximately 50% reduction in abdominal fat compared with those in mice maintained on a control diet [18]. Furthermore, 1.1 μg leucine in 1.0 μL PBS administered by intravenous injection once a day for 7 d did not influence food intake, but modestly blocked body weight reduction in mice maintained on a leucine-deficient diet [19]. In addition to many identified hypothalamic pathways controlling food intake [20], these results suggested that leucine deprivation induces decreased food intake and that leucine also is a key hypothalamic regulator of food intake in mice.…”

“…Finally, the sympathetic nervous system was found to mediate the effect of leucine deprivation on fat loss. These results suggest that hypothalamic CRH is a critical sensor and transporter for stimulating fat loss upon leucine deprivation [19]. To further elucidate the molecular mechanisms underlying hypothalamic CRH regulation of leucine deprivation-stimulated fat loss, Guo's group used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6K1, a major downstream effector of the leucine-deprivation sensing kinase mTOR, in the stimulation of energy expenditure by leucine deprivation.…”

Hypothalamic signaling in anorexia induced by indispensable amino acid deficiency

“…Second, lean mass loss in the VDD groups continued with prolonged diet exposure. IAA deficiency consistently produces enhanced fat loss relative to PF controls (6,7). However, excessive loss of lean mass was not previously demonstrated, perhaps because of the shorter duration of exposure to IAA deficiency.…”

MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4

“…This conclusion is drawn based on results obtained using two different controls, 18 S and U6. Moreover, blocking cAMP-PKA pathway with H89, a widely used PKA inhibitor (34), could reverse the effect of glucagon on the expression of miR-214. This result revealed that expression of miR-214 was indeed regulated by the classical glucagon-GR-PKA pathway, although the direct transcription activators of miR-214 require further investigation.…”