Leucine in food mediates some of the postprandial rise in plasma leptin concentrations

Abstract

In vitro, leptin secretion is regulated at the level of mRNA translation by the rapamycin-sensitive mammalian target of rapamycin (mTOR) and its agonist leucine (Leu). Studies were conducted on meal-trained rats to evaluate the potential physiological relevance of these in vitro findings and the role of Leu in affecting rises in plasma leptin observed after a meal. In the first study, we correlated changes in plasma insulin and Leu to mTOR-signaling pathway activation and plasma leptin at different times during meal feeding. Rapid rises in plasma insulin and Leu, along with mTOR signaling (phosphorylation of eIF4G, S6K1, rpS6, and 4E-BP1) in adipose tissue were observed during the 3-h meal and declined thereafter. Plasma leptin rose more slowly, peaking at 3 h, and was inhibited by rapamycin (0.75 mg/kg) pretreatment. In another experiment, oral Leu or norleucine was provided instead of a meal. Leu and norleucine stimulated a rise in plasma leptin; however, the magnitude was less than the response to a complete meal. In a third study, rats were provided a meal that lacked Leu, branched-chain amino acids, or all amino acids. Stimulation of leptin secretion was reduced approximately 40% in animals provided the Leu-deficient meal. Further reductions were not observed by removing the other amino acids. Thus Leu appears to regulate most of the effects of dietary amino acids on the postprandial rise in plasma leptin but is responsible only for part of the leptin response to meal feeding.

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

“…Several factors make leucine an ideal direct nutrient signal to the brain. First, in contrast to plasma glucose and triglyceride concentrations, which do not change appreciably with feeding, leucine concentrations increased severalfold in circulation during a meal (39). Second, leucine regulates the mTOR-signaling pathway in neurons, in vivo (40).…”

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

“…Administration of BCAAs, particularly leucine, elicits a rise in leptin after 3 h, as shown by Lynch et al (47). This group also showed that norleucine, which does not increase serum insulin, also increases leptin, providing evidence that BCAA increase leptin translation via activation of mTOR (47). Whether amino acids and insulin effects on leptin translation are additive and which factor dominates in vivo will require further research.…”

“…Increasing mTORC1 activity by overexpression of Rheb or dominant negative AMPK increases leptin translation, and this does not require the presence of leptin 5Ј-UTR (14). In the physiological context, independent of their metabolism into glycolytic substrate or TCA cycle intermediates, amino acids can increase leptin within 2-4 h by acting as signaling molecules activating mTOR (47,48,66). However, the downstream events through which activation of mTOR leads to a specific increase in relative rates of leptin biosynthesis, over and above a small increase in general protein synthesis, remain to be determined.…”

“…In pulse-chase experiments, only a fraction, up to 50%, of the labeled leptin that disappeared from cells could be recovered in the medium, suggesting that some of the newly synthesized leptin is degraded within adipose tissue (38). Insulin prevented this intracellular leptin degradation by moving it out of the cells, increasing the half-life of newly (44,47,86) to illustrate that obesity is associated with higher fasting leptin levels and higher meal-induced leptin excursions. We hypothesize that this occurs, at least in part, as a result of increased secretion of preformed leptin from the LFC of the obese.…”

Leptin and mTOR: Partners in metabolism and inflammation

“…45,46 Moreover, several nutrient sensing mediators that activate mTOR in adipose tissue, including insulin, leucine and UDP-N-acetylglucosamine, also induce leptin synthesis. 23,[47][48][49] Could these pathways provide positive feedback for leptin action on adipocytes (Fig. 1)?…”