Leucine acts in the brain to suppress food intake but does not function as a physiological signal of low dietary protein

Abstract

ular injections of leucine are sufficient to suppress food intake, but it remains unclear whether brain leucine signaling represents a physiological signal of protein balance. We tested whether variations in dietary and circulating levels of leucine, or all three branched-chain amino acids (BCAAs), contribute to the detection of reduced dietary protein. Of the essential amino acids (EAAs) tested, only intracerebroventricular injection of leucine (10 g) was sufficient to suppress food intake. Isocaloric low-(9% protein energy; LP) or normal-(18% protein energy) protein diets induced a divergence in food intake, with an increased consumption of LP beginning on day 2 and persisting throughout the study (P Ͻ 0.05). Circulating BCAA levels were reduced the day after LP diet exposure, but levels subsequently increased and normalized by day 4, despite persistent hyperphagia. Brain BCAA levels as measured by microdialysis on day 2 of diet exposure were reduced in LP rats, but this effect was most prominent postprandially. Despite these diet-induced changes in BCAA levels, reducing dietary leucine or total BCAAs independently from total protein was neither necessary nor sufficient to induce hyperphagia, while chronic infusion of EAAs into the brain of LP rats failed to consistently block LP-induced hyperphagia. Collectively, these data suggest that circulating BCAAs are transiently reduced by dietary protein restriction, but variations in dietary or brain BCAAs alone do not explain the hyperphagia induced by a low-protein diet.branched-chain amino acids; protein restriction; hypothalamus; macronutrient; food intake ALTHOUGH THE STUDY OF ingestive behavior historically has focused largely on the regulation of energy homeostasis, the consumption of adequate amounts of protein, specifically essential amino acids (EAAs), is also central to health and survival. Therefore, it seems likely that physiological systems exist to ensure sufficient protein intake. Alterations in dietary protein content can have profound effects on food intake, with diets high in protein suppressing food intake and diets moderately low in protein increasing food intake (2,11,18,23,38,39). Furthermore, when given the choice between diets that differ in protein content, many species will self-select between diets to ensure adequate consumption of protein (16,24,27), often at the expense of carbohydrate and fat (9,19,31).Despite these behavioral observations, the mechanism regulating protein intake is largely unknown (21). Recent work has focused on the branched-chain amino acid (BCAA) leucine as a potential protein signal. Intracerebroventricular injections of leucine suppress food intake and regulate key signaling systems (mTOR/AMPK) within hypothalamic neurons, while increased dietary leucine content reproduces the anorectic effects of a high-protein diet (3,5,23,29). While these data demonstrate that administration of excess leucine either to the diet or the brain is sufficient to suppress food intake, it remains unclear whether physiological fluctua...

Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2

“…Our previous work indicated that WT mice and rats exhibit significant increases in food intake when exposed to LP diet for 2 weeks (Laeger et al, 2014a; Laeger et al, 2014b; Morrison et al, 2007), and here this hyperphagic response extended to the entire 27 week experiment (Figure 1H). The increase in food intake was accompanied by a persistent increase in EE, as demonstrated by the increase in EE in WT-LP mice after 11 weeks on diet (Figure 1G and S2), and by the fact that the LP-induced hyperphagia did not produce weight gain.…”

“…Dietary protein restriction is known to increase both food intake and energy expenditure (Gosby et al, 2014; Hasek et al, 2010; Laeger et al, 2014a; Laeger et al, 2014b; Morrison et al, 2007; Rothwell and Stock, 1987; Rothwell et al, 1983; Simpson and Raubenheimer, 1997, 2005; White et al, 2000). We observe similar effects in the current data, and demonstrate that these changes are persistent over the entire 6 month experiment.…”

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health

“…In mice placed on a Low AA diet, this may be explained in part by an FGF21-mediated increase in energy expenditure (Laeger et al, 2014a), but mice eating a diet specifically reduced in the BCAAs do not have increased FGF21 or increased energy expenditure; the mechanism for this remains to be determined. Interestingly, a recent study in Sprague-Dawley rats determined that diets with reduced dietary BCAAs do not stimulate hyperphagia (Laeger et al, 2014b); whether this reflects differences between mice and rats, or experimental differences in the length of diet feeding and the degree of BCAA restriction remains to be determined.…”

Central Amino Acid Sensing in the Control of Feeding Behavior

“…Subsequently, several groups confirmed that administration of physiologically relevant amounts of leucine into the 3rd ventricle or discrete brain nutrient-sensing regions of fasted rodents reduces energy intake during the subsequent refeeding period (26, 86–88). This anorectic response is not produced by other branched-chain amino acids or any aromatic amino acids (26, 87), is not accompanied by the development of conditioned taste aversion (26, 86), persists for 24 h, and produces a significant decrease in body weight gain (26, 86), as summarized in Table 1. Brain leucine levels are increased following a meal, and brain leucine administration reduces food intake, suggesting that brain amino acid levels may constitute a signal of energy and/or protein availability detected by brain nutrient-sensing regions that modulate homeostatic feeding-regulatory circuits.…”

“…In contrast, marginally low-protein diets (LP, 8–10% of energy as protein in rats) with balanced EAA profiles induce a hyperphagic response restoring nitrogen and EAA intakes which, together with various metabolic adaptions, are sufficient to enable growth (87, 91, 104–108). Conversely, high-protein diets (HP, 20–70% of energy as protein) produce a sustained decrease in energy intake that is not caused by taste aversion even at very high-protein levels (109, 110).…”