The Journal of Clinical Investigation COMMENTARY Hungry for your alanine: when liver depends on muscle proteolysis Theresia Sarabhai1,2 and Michael Roden1,2,3 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany. 2German Center for Diabetes Research, München-Neuherberg, Germany. 3Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. β-oxidation and the acetyl-CoA pool, which Fasting requires complex endocrine and metabolic interorgan crosstalk, allosterically activates pyruvate carboxylase flux (V ), and which, together with glycerol which involves shifting from glucose to fatty acid oxidation, derived from PC adipose tissue lipolysis, in order to preserve glucose for the brain. The as substrate, maintains the rates of hepatic gluconeogenesis and endogenous glucose glucose-alanine (Cahill) cycle is critical for regenerating glucose. In this issue production (V ) (8). of JCI, Petersen et al. report on their use of an innovative stable isotope EGP tracer method to show that skeletal muscle–derived alanine becomes rate Liver–skeletal muscle controlling for hepatic mitochondrial oxidation and, in turn, for glucose metabolic crosstalk production during prolonged fasting. These results provide new insight Other metabolic pathways are also known into skeletal muscle–liver metabolic crosstalk during the fed-to-fasting to connect skeletal muscle and liver. The transition in humans. Cori cycle describes the shuttling of lactate derived from skeletal muscle anaerobic gly- colysis to the liver to feed gluconeogenesis upon intensive exercising. In addition, skel- etal muscle contributes to fasting metabo- Adaptive response to fasting (5). During the transition from the fed to lism, not only by glycogenolysis and glycol- Adaptation to fasting is a fascinating phys- the early fasted state, the liver switches ysis yielding pyruvate, but also by protein iological phenomenon allowing organ- from glycogen storage to glucose produc- breakdown yielding amino acids (Figure isms to maintain energy supply to tissues tion by glycogen breakdown as well as by 1). These pathways converge via alanine despite declining energy stores. During gluco neogenesis from noncarbohydrate transaminase (ALT), which transfers amino evolution, multiple mechanisms evolved to precursors, such as lactate, glycerol, and groups from amino acids to pyruvate to form counter the threat of starvation. Periods of branched-chain amino acids (6). Prolonged and release alanine and thereby prevent famine and starvation have likely selected fasting requires the liver to shift from car- skeletal muscle from rapidly accumulating genotypes featuring adaptive responses, bohydrate oxidation to β- oxidation of free toxic ammonium (9). The latter glucose-al- such as hepatic insulin resistance, e.g., by fatty acids (FFAs) so that ketone bodies anine cycle, also known as the Cahill cycle, insulin receptor mutation in cave-dwelling become the main energy source (7). allows glucose to regenerate from alanine in Astyanax mexicanus fish (1) or insulin resis- In a previous study, the researchers the liver by a series of reactions (7). Although tant subtypes of type 2 diabetes prone to developed a positional isotopomer nuclear this interorgan communication is fairly pro- nonalcoholic fatty liver disease (NAFLD) magnetic resonance tracer analysis (PINTA) ductive, yielding 2 mol ATP per 1 mol glu- (2). On the other hand, various concepts to elucidate the interaction between adipose cose oxidized in muscle and yielding 2 mol of dietary restriction, e.g., interval/inter- tissue and liver crosstalk during starvation of carbon-3 glucose precursors from alanine, mittent fasting (3) or very low caloric diets in rodents (8). During starvation, the decline energetic efficiency decreases with glucone- (4), may help to combat the current obesity in hepatic glycogenolysis results in a fall of ogenesis and urea synthesis (Figure 1). As a and type 2 diabetes epidemic. plasma leptin, which stimulates the hypo- result, the transition from the fed to the fast- The liver plays the key role in main- thalamic-pituitary-adrenal axis (HPA) and, ed state shifts the control of energy metabo- taining blood glucose concentrations for in turn, adipose tissue lipolysis with release lism and glucose production from the liver obligate glucose utilizers (central nervous of FFA and glycerol (Figure 1). In the liver, to adipose tissue and skeletal muscle, and system, red blood cells, renal medulla) the increase in FFA levels stimulates hepatic alanine may become an important substrate, maintaining glucose homeostasis and regu- lating hepatic energy metabolism. Related Article: p. 4671 Alanine-to-glucose conversion during fasting in humans Conflict of interest: MR is on scientific advisory boards for Bristol-Myers Squibb, Lilly, Gilead, Novo Nordisk, Servier, In humans, examining the metabolic path- TARGET PharmaSolutions, and Terra Firma and receives investigator-initiated research support from Boehringer Ingelheim, Nutricia/Danone, and Sanofi-Aventis. ways of interorgan crosstalk has been lim- Copyright: © 2019, American Society for Clinical Investigation. ited by several factors. Measurements of Reference information: J Clin Invest. 2019;129(11):4563–4566. https://doi.org/10.1172/JCI131931. hepatic metabolite concentrations or flux jci.org Volume 129 Number 11 November 2019 4563 COMMENTARY The Journal of Clinical Investigation Figure 1. Liver–skeletal muscle crosstalk fuels metabolism in starvation. The Cahill cycle allows for recycling of hepatic glucose from skeletal muscle + alanine via ALT and for detoxification of ammonium ions (NH4 ) from proteolysis via the hepatic urea cycle. In 60-hour fasted humans, the nearly unchanged gluconeogenesis, as assessed from VPC, indicates that reduced hepatic glycogenolysis accounts for the decrease in VEGP. The decrease in VCS occurred in parallel to a rise in the β-hydroxy-butyrate/acetoacetate ratio (β-OHB/AcAc) suggesting that the redox potential regulates VCS. Of note, alanine infusion partially reversed these alterations under conditions of already stimulated hepatic mitochondrial oxidation resulting from substrate supply and endocrine stimulation. CI, citrate; FA-CoA, fatty acyl–coenzyme A; GH, growth hormone; α-KG, α-ketoglutarate; βOX, β-oxidation; OA, oxaloacetate; PEP, phospho- enolpyruvate; PEPCK, PEP carboxykinase; TAG, triglycerides; T3, triiodothyronine. rates cannot be performed invasively due chondrial oxidation from citrate synthase 30%, respectively. Next, they infused to ethical considerations precluding liver flux (VCS) (11). In addition, they assessed alanine intravenously in 60-hour fasted biopsies for physiological studies. Nonin- systemic alanine turnover using [3-13C]ala- humans to match the higher alanine turn- vasive in vivo magnetic resonance spec- nine infusion as well as the hepatic mito- over observed after 12 hours of fasting, + troscopy is expensive, not generally avail- chondrial redox state (NADH:NAD ) from which raised VEGP and VPC and markedly able, and confined to certain metabolites. the ratio of plasma β-hydroxybutyrate/ace- stimulated VCS, by approximately 70%. Petersen and colleagues combined min- toacetate concentrations. The alanine-stimulated gluconeogenesis imal invasive techniques to examine the After 60 hours of fasting, VEGP (VPC) occurred under conditions of sup- glucose-alanine cycle during short-term decreased by more than 20% despite posedly maximal stimulation by glucagon (12 hour) and prolonged (60 hour) fasting largely unchanged VPC, indicating that and FFA from adipose tissue lipolysis. Of in healthy humans (10). They applied their the reduction in glucose production was note, the rise of VPC correlated with mito- recently described PINTA method and mainly due to decreased net glycogeno- chondrial oxidation, which indicates an infused three stable-isotope–labeled sub- lysis (Figure 1). Hepatic VCS and endog- important role of skeletal muscle–derived strates that allowed for simultaneous mea- enous alanine turnover decreased by alanine as rate controlling for hepatic surement of VEGP, VPC, and hepatic mito- approximately 50% and approximately mitochondrial oxidation and, in turn, 4564 jci.org Volume 129 Number 11 November 2019 The Journal of Clinical Investigation COMMENTARY gluconeogenesis and glucose produc- In this context, the complementary rodent hepatic mitochondrial oxidation, results tion in starving humans (10). At present, study by Petersen et al. demonstrated that that will have important implications for these results cannot yet be generalized the hypoleptinemia-induced glucose-FFA metabolic dysfunction in obesity, type 2 because the study exclusively compared cycle during a 48-hour fast is indeed medi- diabetes, and NAFLD (2). short- with long-term fasted healthy lean ated by an increase in glucocorticoids, young men. Furthermore, hormones, which stimulates adipose lipolysis to Acknowledgments aging, sarcopenia, obesity, and diabetes increase hepatic acetyl-CoA content and The authors’ work is supported by grants mellitus can affect protein turnover and allosterically activate VPC flux (8). from the German Federal Ministry of possibly influence the contribution of Modulation of hepatic mitochondri- Health and Ministry of Culture and Sci- the glucose-alanine cycle to liver metab- al oxidation is not only involved in the ence of the state North Rhine-Westphalia