Role of AMPK and mTOR in the hypothalamus and brainstem for the reduction of food intake by the amino acids leucine and serine
Final Report Abstract
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. Furthermore, when given the choice between diets that differ in protein content, many species will self-select between diets to ensure the consumption of adequate protein. Despite these behavioral observations, the mechanism regulating protein intake is largely unknown. 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. While these data demonstrate that administration of excess leucine either to the diet or to the brain is sufficient to suppress food intake, it remains unclear whether physiological fluctuations in circulating or brain leucine actually contribute to the regulation of dietary protein intake or selection. Here we use the adaptive hyperphagia that occurs in response to a low protein diet to test the physiological role of dietary leucine and BCAAs in the detection of protein restriction. We observe a significant increase in food intake in rats within 48 hours of exposure to a low protein (LP) diet. Although we observe transient changes in plasma and brain amino levels, these changes rapidly normalize and are not consistent with the hyperphagia. We also find no direct evidence that changes in circulating or brain leucine or BCAAs contribute to LP-induced hyperphagia. Our data indicate that rats are completely insensitive to reductions in dietary BCAAs that mimic the LP diet, and that supplementing dietary BCAAs fails to block LP-induced hyperphagia. Finally, brain infusion of amino acids fails to block LP-induced hyperphagia. Taken together, our data indicate that dietary and circulating BCAAs, including leucine, are neither necessary nor sufficient for the hyperphagia induced by a LP diet. Considering our evidence that leucine is a pharmacological but not a physiological signal of dietary protein restriction, we have sought to identify other potential mediators of the metabolic and behavioral response to dietary protein restriction. We focused on liver-derived signals, as our data indicate that protein restriction induces marked changes in the liver. The fibroblast growth factor 21 (FGF21) was initially described as a peptide hormone produced by the liver in response to starvation. Our recent data demonstrate that FGF21 is acutely increased by protein restriction, and that dietary protein restriction underlies the previously described increases in FGF21 during starvation or a ketogenic diet. Using FGF21-deficient mice, we also demonstrate that FGF21 is required for the metabolic and behavioral response to protein restriction, as these mice fail to exhibit the changes in food intake, energy expenditure or body weight that are observed in wildtype mice on a low protein diet. Finally, we demonstrate that the serine/threonine kinase general control nonderepressible 2 (GCN2) contributes to the induction of hepatic FGF21 during protein restriction. As such, these novel data fundamentally redefine the physiological roles of FGF21 while also identifying a previously undescribed mechanism for the detection of protein restriction. Our data show that FGF21 may be the first hormone that specifically acts as a signal of dietary protein.
Publications
- Amino acid-dependent regulation of food intake: is protein more than the sum of its parts? J Physiol 2013; 591(22): 5417-5418
Laeger T and Morrison CD
- FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124(9): 3913-3922
Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Münzberg H, Hutson S, Gettys TW, Schwartz MW, and Morrison CD
(See online at https://doi.org/10.1172/JCI74915) - Leucine acts in the brain to suppress food intake but does not function as a physiological signal of low dietary protein. Am J Physiol Regul Integr Comp Physiol 2014; 307(3): R310-20
Laeger T, Reed SD, Henagan TM, Fernandez DH, Taghavi M, Addington A, Münzberg H, Martin RJ, Hutson SM, and Morrison CD
(See online at https://doi.org/10.1152/ajpregu.00116.2014) - Protein-dependent regulation of feeding and metabolism (invited Review). Trends Endocrinol Metab 2015; 26(5): 256-262
Morrison CD and Laeger T
(See online at https://doi.org/10.1016/j.tem.2015.02.008)
