Cellular Sensors of Feast and Famine

Cellular sensors of feast and famine

Eric Ravussin

J Clin Invest. 2002;109(12):1537-1540. https://doi.org/10.1172/JCI16045.

Commentary

In response to changes in environmental conditions, animals and humans alike can initiate physiological regulatory mechanisms to assure survival. For example, when food is scarce, the body becomes “thrifty”, and conversely, when it is abundant, physiological “unthrifty” mechanisms are initiated. Recent work has uncovered novel cellular mechanisms of fuel sensing that contribute to these shifts and has established a potential relationship between these responses and the common metabolic phenotype of insulin resistance. The first such mechanism to be identified depends on malonyl Co-A, which allosterically inhibits carnitine palmitoyl transferase (CPT1). Because this enzyme controls mitochondrial uptake, and hence oxidation, of long-chain fatty acyl-CoAs (see Ruderman for review, ref. 1), malonyl-CoA can act as a fuel sensor to regulate the rate of fatty acid oxidation in muscle (Figure 1). Ten years ago, Marshall et al. (2) suggested that another fuel-sensing mechanism, this one dependent on the hexosamine biosynthesis pathway (blue arrows in Figure 1), mediates the cellular response to excess environmental glucose. These authors proposed that metabolism of glucose by this route, which typically represents 1-3% of total glucose metabolism, generates a cellular satiety signal that leads to decreased glucose uptake by insulin-sensitive cells. In this issue of the JCI, Obici et al. (3) propose that the hexosamine pathway is not only involved in glucose metabolism and insulin resistance, but may […]

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See related article, pages 1599–1605. Eric Ravussin

Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana, 70808-4124, USA. Phone: (225) 763-3186; Fax: (225) 763-3030; E-mail: [email protected].

J. Clin. Invest. 109:1537–1540 (2002). doi:10.1172/JCI200216045.

In response to changes in environ- tional regulation in the adaptive affluence. The tendency of popula- mental conditions, animals and response to energy surfeit. tions to gain weight under current humans alike can initiate physiologi- conditions of plenty should therefore cal regulatory mechanisms to assure Energy balance and be considered as a normal physiologic survival. For example, when food is the “thrifty genotype” response to what has been called an scarce, the body becomes “thrifty”, and Historically, most human popula- “obesigenic” environment. Large dif- conversely, when it is abundant, phys- tions have evolved in environments in ferences in individuals’ propensity to iological “unthrifty” mechanisms are which large amounts of physical weight gain persist in the face of this initiated. Recent work has uncovered effort were required to obtain food in general trend (4, 5), probably because novel cellular mechanisms of fuel sens- limited supply. Thus, it is not surpris- the “thrifty genotype”, as James Neel ing that contribute to these shifts and ing that the human genome harbors termed it, is distributed unevenly has established a potential relation- many genes that predispose to posi- among individuals (6, 7). ship between these responses and the tive energy balance and obesity and One hundred years ago, Neumann common metabolic phenotype of fewer that protect against the effect of made the seminal observation that insulin resistance. The first such mechanism to be identified depends on malonyl Co-A, which allosterically inhibits carnitine palmitoyl transferase (CPT1). Because this enzyme controls mitochondrial uptake, and hence oxidation, of long- chain fatty acyl-CoAs (see Ruderman for review, ref. 1), malonyl-CoA can act as a fuel sensor to regulate the rate of fatty acid oxidation in muscle (Fig- ure 1). Ten years ago, Marshall et al. (2) suggested that another fuel-sensing mechanism, this one dependent on the hexosamine biosynthesis pathway (blue arrows in Figure 1), mediates the cellular response to excess environmental glucose. These authors proposed that metabolism of glucose by this route, which typically represents 1-3% of total glucose metabolism, generates a cellular satiety signal Figure 1 Two cellular fuel-sensing pathways. The hexosamine biosynthesis pathway and the malonyl Co-A that leads to decreased glucose uptake system are proposed to modulate energy consumption by muscle and other tissues in response to by insulin-sensitive cells. changing levels of metabolic fuels. Following its entry into the cell via the glucose transport system, In this issue of the JCI, Obici et al. glucose is phosphorylated into glucose-6-phosphate (G-6-P), which is primarily utilized by the (3) propose that the hexosamine pathways of glycogen synthesis and glycolysis. Only 1–3% of the glucose entering the cells is divert- pathway is not only involved in glu- ed to glucosamine-6-phostate by the rate-limiting enzyme glutamine:fructose-6-phosphate ami- cose metabolism and insulin resist- dotransferase (GFAT) (blue arrows). The end product of this pathway, uridinediphosphoglucose- ance, but may also be one of the bio- N-acetylglucosamine (UDP-GlcNAc) serves as substrate for virtually all glycosylation pathways in chemical links between nutrient the cells. Glucosamine enters the pathway directly after the rate-limiting step of GFAT, therefore availability and cellular energy metab- mimicking a signal of excess glucose or nutrient. The second fuel-sensing pathway is that of mal- olism. The activation or inhibition of onyl-CoA. Increased cytosolic citrate from both the Krebs cycle and beta-oxidation contribute to increased Acetyl-CoA. Acetyl-CoA is the precursor of malonyl-CoA, a conversion that involves this fuel sensing pathway may, there- acetyl-CoA carboxylase 2 (ACC2). The primary role of malonyl-CoA is to regulate the rate of fat fore, play an important role in the oxidation via its allosteric inhibition of carnitine palmitoyl transferase (CPT1), the enzyme respon- regulation of energy balance. Howev- sible for converting long-chain fatty acyl-CoA into long-chain acyl-carnitine. Because the availability er, their present data raise significant of Acetyl-CoA and the activity of ACC2 can each influence the concentration of malonyl-CoA, both questions about the role of transcrip- can alter the balance between fat storage and fat oxidation.

The Journal of Clinical Investigation | June 2002 | Volume 109 | Number 12 1537 of gene expression (10). Mammals have developed an indirect mechanism by which the beta cells in the pancreas modulate insulin secretion by monitoring glucokinase and ATP changes, which in turn reflect the amount of intracellular glucose that undergoes glycolysis (11). Other mammalian cell types can also sense glucose and respond by repressing or inducing the necessary genes for adaptive responses. The 10-year-old hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway has gained momentum (2). In skeletal muscle and adipose tissue, following glucose transport and phosphoryla- Figure 2 tion, glucose-6-phosphate is primari- The negative feedback model for the regulation of body weight. In this model, peripheral signals ly used for glycogenesis or glycolysis from energy stores (adipose tissue, muscle, and liver) as well as hormonal and gastrointestinal sig- (Figure 1). A small proportion, how- nals act on the central controllers in the brain, indicating the state of the external and internal envi- ever, is shunted to the hexosamine ronment as they relate to food, metabolic rate, and activity behaviors. In turn, the central con- pathway by the rate-limiting enzyme trollers integrate these signals and transduce these messages into efferent signals governing the glutamine:fructose-6-phosphate behavioral search for the acquisition of food, as well as modulating its subsequent deposition into energy storage compartments, such as adipose tissue, liver, and muscle. Afferent signals, efferent amidotransferase (GFAT), which signals, and central controllers can all be influenced by an organism’s genetic makeup, hence the converts fructose-6-phosphate to inter-individual variability in weight change in response to a perturbed energy balance. glucosamine-6-phosphate. Because the end product of this pathway, uridinediphosphoglucose-N-acetyl- the increase in body weight in balance. In response, these controllers glucosamine (UDP-GlcNAc), serves response to overfeeding is not pro- engage a series of efferent neural and as a substrate for most glycosylation portional to the excess ingested ener- neuroendocrine signals that are pathways, the flux through the hex- gy (8). To explain this discrepancy, he specifically geared to counteract the osamine pathway could well affect hypothesized that some of the energy excess caloric intake. These signals the stability and activity of many pro- ingested, in excess of normal require- eventually decrease appetite and/or teins, ultimately altering cellular pat- ments, was dissipated as heat or increase energy expenditure, thus terns of gene expression. “Luxuskonsumption”. This was the causing a decrease in the energy As reviewed by Rossetti (12), sever- first description of what is now stored in the body. Conversely, during al studies have shown that increased referred to as adaptive thermogenesis. periods of food restriction, opposing flux of fructose-6-phosphate into the Over the past five decades, scientists signals protect the body against ener- hexosamine biosynthesis pathway have tried to identify the mechanisms gy loss by increasing hunger and decreases glucose uptake in vivo in underlying the variability in adaptive food-seeking behaviors and decreas- animals and in vitro in isolated cells. thermogenesis and its consequence ing energy expenditure. Any compo- Similarly, when GFAT is over- on weight gain in response to over- nent of this feedback loop can influ- expressed in transgenic animals, the feeding. First, at the whole-body level, ence the robustness of the adaptive skeletal muscle becomes insulin- it became clear that energy surfeit can response. More recent research has resistant, β cells secrete excess be sensed and that signals are sent to focused on the potential molecular insulin, and the liver synthesizes central controllers. These controllers mechanisms that explain this excess fatty acids in parallel to the then orchestrate a physiological response to fuel availability at the cel- increased flux through the hex- response, which tends to limit food lular level. osamine pathway (13). Consistent intake and increase energy metabo- with the role of the hexosamine lism (Figure 2). This feedback model, Glucose sensing mechanisms biosynthesis pathway as a fuel-sens- originally proposed by Bray (9), still Because the availability of carbon ing system, glucosamine infusion represents the working hypothesis sources can fluctuate widely, organ- during a hyperinsulinemic eug- that is used to explain the large vari- isms from prokaryotes to humans lycemic clamp, which bypasses the ability in body weight gain in require means to sense the level of GFAT-dependent step (Figure 1), response to excess energy intake. glucose, the major source of energy in causes a marked decrease in glucose According to this model, in response most cases. For example, two differ- uptake (14). Whether increased avail- to overfeeding, the gastro-intestinal ent glucose-sensing signal transduc- ability of free fatty acids causes tract and the adipose tissue, among tion pathways have been identified in insulin resistance via an increased others, provide endocrine and neural the yeast Saccharomyces cerevisiae, one flux into the hexosamine pathway is signals to brain controllers of energy for repression and one for induction still controversial (15, 16). The effect

1538 The Journal of Clinical Investigation | June 2002 | Volume 109 | Number 12 of glucosamine infusion on insulin skeletal muscle. Counter to the glu- response to overfeeding, in parallel to sensitivity in humans is also unclear; cosamine infusion paradigm, howev- a moderate 35% increase in the mus- one study found a modest decrease in er, oxygen consumption was not cle level of UDP-GlcNAc, the pro- insulin sensitivity (17), but another decreased (on the contrary, as expect- posed cellular signal of energy sur- did not (18). ed it was increased by 7%) in response feit. It is therefore conceivable that to overfeeding. The regulation of the the duration and magnitude of the Gene expression and cellular previously identified set of mRNAs overfeeding was not sufficient to energy expenditure thus appears not to be part of the cause a larger stimulation of the hex- The new study by Obici et al. (3) physiological process of increased osamine pathway, as evidenced by the emphasizes that the hexosamine energy dissipation, at least not in lack of stimulation of UCP1 and the biosynthesis pathway is not only a muscle cells under conditions of modest increase in energy expendi- major mediator of carbohydrate overfeeding. This unexpected result ture. The discrepancy between the metabolism, but may also represent a may suggest that the acute response responses in skeletal muscle versus biochemical link between nutrient to overfeeding or glucosamine excess brown adipose tissue is intriguing availability and the molecular cellular is controlled post-transcriptionally. and implies that gene regulation in response in terms of energy expendi- Conceivably, the transcriptional response to a change in the hex- ture. The authors tested the hypothe- response they observe serves another osamine pathway flux is tissue-spe- sis that the hexosamine biosynthesis purpose in energy homeostasis, per- cific. However, it is likely that both pathway represents a signal of energy haps setting the stage for the muscle tissues participate in concert in the “overflow,” which, they proposed, cells to return to normal or even adaptive response to overfeeding. would initiate compensatory respons- lower levels of energy expenditure This report raises many questions es in skeletal muscle gene expression. once the surfeit has passed. regarding the importance of the hex- Employing their previously developed osamine fuel-sensing pathway in the paradigm of hyperinsulinemic eug- Outstanding questions variability among strains of animals lycemic clamp in association with glu- As with any new discovery, the study or among individuals in their cosamine infusion to mimic nutrient by Rossetti’s laboratory provides response to feast or famine. Is this excess, they first measured muscle more questions than answers. The pathway induced differently in obesi- gene expression using microarrays. authors conclude that “in keeping ty-prone and obesity-resistant ani- After a preliminary exploration of with the Neel’s thrifty genotype mals? Does the composition of the genes that were up- or down-regulat- hypothesis, a sustained increase in diet influence the intracellular con- ed, they confirmed their findings by the availability of nutrients may trig- centration of the endproduct of the Northern blots. Surprisingly, they did ger biological actions designed to pathway (UDP-GlcNAc) in a way par- not observe an increase, but rather a increase the efficiency of energy stor- alleling the changes in metabolic gene decrease in the expression of mRNAs age by limiting fuel oxidation and expression? Is the response to over- encoding crucial mitochondrial pro- ATP production”. However, a thrifty feeding influenced by the state of teins involved in oxidative phospho- organism, as envisioned by Neel, insulin resistance of the animals? Per- rylation and substrate oxidation. In should respond by a decline in ener- haps so, since diabetic animals pre- particular, glucosamine down-regu- gy metabolism during times of sumably have high intracellular con- lated expression of one or more sub- famine, and an increase in energy centrations of UDP-GlcNAc. Is the units in all but one of the respiratory metabolism (even though modest) hexosamine pathway equally impor- chain complexes and of various gene during times of plenty (19). Clearly, tant in other important tissue for products involved in fatty acid oxida- the clamp/glucosamine paradigm energy balance, such as the liver? Since tion, mitochondrial substrate shut- did not cause the expected increase in changes in gene expression are tissue- tling, or the Krebs cycle. On the other energy expenditure during a condi- specific, studies are necessary to fully hand, the expression of the same tion mimicking energy excess. understand the molecular mecha- genes (plus uncoupling protein-1) was Why should the expression of genes nisms by which the hexosamine increased in brown adipose tissue. involved in energy dissipation biosynthesis pathway modulates the Consistent with the down-regula- decrease in a situation known to expression of genes involved in energy tion of energy expenditure genes in increase energy expenditure? It metabolism. The hexosamine biosyn- muscle following glucosamine infu- should be noted that the authors did thesis pathway has also been shown to sion, the rats exhibited a decrease in not measure energy metabolism dur- regulate leptin expression and secre- oxygen consumption and energy ing the procedure but only during tion in adipose and muscle cells alike expenditure in the hours following the 17 hours following the clamp, so (20). Is there an indirect role of this the clamp procedure. To test this the effects of the gene down-regula- pathway on body weight regulation association in a more physiological tion they observed may not correlate via regulation of leptin biosynthesis? manner, Obici et al. tested the effects with the expected physiological All these questions will need clarifica- of overfeeding in vivo. Although they response. Interestingly, in the more tion. The answers will help narrow the found no evidence that the defined physiological situation of overfeed- gap in our understanding of whole- set of genes were upregulated in ing, the adaptive response to energy body physiology and of molecular brown adipose tissue under these excess was an increase and not a mechanisms that control energy stor- conditions, they did indeed confirm decrease in energy expenditure. Oxy- age and consumption in muscles and that they were down regulated in gen consumption increased by 7% in other key tissues.

The Journal of Clinical Investigation | June 2002 | Volume 109 | Number 12 1539 1. Ruderman, N.B., et al. 1999. Malonyl-CoA, fuel 7. Neel, J.V. 1999. The “thrifty genotype” in 1998. glycemic but not in hyperglycemic conscious sensing, and insulin resistance. Am. J. Physiol. Nutr. Rev. 57:S2–S9. rats. J. Clin. Invest. 96:132–140. 276:E1–E18. 8. Neumann, R. 1902. Experimentelle Beitrage zur 15. Hawkins, M., et al. 1997. Role of the glu- 2. Marshall, S., Bacote, V., and Traxinger, R.R. Lehre von dem täglichen Nahrungsbedarf des cosamine pathway in fat-induced insulin resist- 1991. Complete inhibition of glucose-induced Menschen unter besonderer Berücksichtigung ance. J. Clin. Invest. 99:2173–2182. desensitization of the glucose transport system der notwendigen Eiweissmenge. Arch. Hyg. 16. Choi, C.S., Lee, F.N., and Youn, J.H. 2001. Free by inhibitors of mRNA synthesis. Evidence for 45:1–87. fatty acids induce peripheral insulin resistance rapid turnover of glutamine:fructose-6-phos- 9. Bray, G.A. 1991. Obesity, a disorder of nutrient without increasing muscle hexosamine phate amidotransferase. J. Biol. Chem. partitioning: the MONA LISA hypothesis. pathway product levels in rats. Diabetes. 266:10155–10161. J. Nutr. 121:1146–1162. 50:418–424. 3. Obici, S., et al. 2002. Identification of a bio- 10. Johnston, M. 1999. Feasting, fasting and fer- 17. Monauni, T., et al. 2000. Effects of glucosamine chemical link between energy intake and ener- menting. Glucose sensing in yeast and other infusion on insulin secretion and insulin action gy expenditure. J. Clin. Invest. 109:1599–1605. cells. Trends Genet. 15:29–33. in humans. Diabetes. 49:926–935. doi:10.1172/JCI200215258. 11. Newgard, C.B., and McGarry, J.D. 1995. Meta- 18. Pouwels, M.J., et al. 2001. Short-term glu- 4. Bouchard, C., et al. 1990. The response to long- bolic coupling factors in pancreatic beta-cell cosamine infusion does not affect insulin sen- term overfeeding in identical twins. N. Engl. J. signal transduction. Annu. Rev. Biochem. sitivity in humans. J. Clin. Endocrinol. Metab. Med. 322:1477–1482. 64:689–719. 86:2099–2103. 5. Levine, J.A., Eberhardt, N.L., and Jensen, M.D. 12. Rossetti, L. 2000. Perspective: hexosamines and 19. Leibel, R.L., Rosenbaum, M., and Hirsch, J. 1999. Role of nonexercise activity thermogene- nutrient sensing. Endocrinology. 141:1922–1925. 1995. Changes in energy expenditure resulting sis in resistance to fat gain in humans. Science. 13. McClain, D.A. 2002. Hexosamines as mediators from altered body weight. N. Engl. J. Med. 283:212–214. of nutrient sensing and regulation in diabetes. 332:621–628. 6. Neel, J.V. 1962. Diabetes mellitus: a “thrifty” J. Diabetes Complications. 16:72–80. 20. Wang, J., et al. 1998. A nutrient-sensing path- genotype rendered detrimental by “progress”? 14. Rossetti, L., et al. 1995. In vivo glucosamine way regulates leptin gene expression in muscle Am. J. Hum. Genet. 14:353–363. infusion induces insulin resistance in normo- and fat. Nature. 393:684–688.

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