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...
Elevation of dietary or brain leucine appears to suppress food intake via a mechanism involving mTOR, AMPK and/or branched chain amino acid (BCAA) metabolism. Mice bearing a deletion of mitochondrial branched chain amino transferase (BCATm), which is expressed in peripheral tissues (muscle) and brain glia, exhibit marked increases in circulating BCAAs. Here we test whether this increase in circulating BCAAs alters feeding behavior and brain neuropeptide expression. Circulating and brain levels of BCAAs were increased 2-4 fold in BCATm-deficient mice (KO). KO mice weighed less than controls (25.9 vs. 20.4g, P < 0.01), but absolute food intake was relatively unchanged. In contrast to wildtype mice, KO mice preferred a low BCAA diet to a control diet (P < 0.05), but exhibited no change in preference for low vs. high protein diets. KO mice also exhibited low leptin levels and increased hypothalamic NPY and AgRP mRNA. Normalization of circulating leptin levels had no effect on either food preference or the increased NPY and AgRP mRNA expression. If BCAAs act as signals of protein status, one would expect reduced food intake, an avoidance of dietary protein, and a reduction in neuropeptide expression in BCATm-KO mice. Instead, these mice exhibit increased expression of orexigenic neuropeptides and an avoidance of BCAAs but not high protein. These data thus suggest either that BCAAs do not act as physiological signals of protein status, or that the loss of BCAA metabolism within brain glia impairs the detection of protein balance.
The goal of this study was to generate murine models for Maple Syrup Urine Disease (MSUD), enabling elucidation of the biochemical basis for the pathology of this inborn error of branched chain amino acid (BCAA) metabolism. As expected, loss of the E1α subunit (E1α KO) of the E1 dehydrogenase enzyme resulted in a mouse that died 24hr after birth. KO pups showed elevated levels of BCAA and branched chain α‐keto acids (BCKA) in their plasma and body tissues. The heterozygote mice (Het) were viable with ~50% of E1 enzyme levels found in wild type (WT) mouse tissues. When fed a 60% protein diet (HPD), Het food intake was lower, whereas body weight, percent fat, and plasma BCAAs were significantly higher than WT mice. To determine if deletion of E1 in brain could reproduce the MSUD brain pathology, a neuronal E1α KO was generated using the nestin‐Cre promoter (Nes‐E1α KO). These mice did not exhibit an MSUD phenotype even though E1 enzyme protein was also lowered in tissues outside the brain. The Nes‐E1α KO mice were sensitive to a HPD exhibiting higher percent of body fat elevated plasma BCAA and BCKA and food aversion. The data suggest that BCAA and/or BCKA may play a role in food intake and fat metabolism. Elevated peripheral BCAA and BCKA are also required to induce the MSUD brain pathology. (Funding: Virginia Tech)
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