Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Organismal Carbohydrate and Lipid Homeostasis D. Grahame Hardie College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom Correspondence: [email protected] SUMMARY All living organisms maintain a high ATP:ADP ratio to drive energy-requiring processes. They therefore need mechanisms to maintain energy balance at the cellular level. In addition, multi- cellular eukaryotes have assigned the task of storing energy to specialized cells such as adipo- cytes, and therefore also need a means of intercellular communication to signal the needs of individual tissues and to maintain overall energy balance at the whole body level. Such signal- ing allows animals to survive periods of fasting or starvation when food is not available and is mainly achieved by hormonal and nervous communication. Insulin, adipokines, epinephrine, and other agonists thus stimulate pathways that regulate the activities of key enzymes involved in control of metabolism to integrate organismal carbohydrate and lipid metabolism. Overnu- trition can dysregulate these pathways and have damaging consequences, causing insulin re- sistance and type 2 diabetes. Outline 1 Introduction 8 Liver—long-term regulation of gluconeogenesis via effects on gene expression 2 Maintaining energy homeostasis— hormones and adipokines 9 Liver—regulation of fatty acid, triglyceride, and cholesterol metabolism 3 Muscle—acute activation of glycogen breakdown 10 Adipocytes—regulation of fatty acid metabolism 4 Muscle—acute regulation of glucose uptake and glycogen synthesis 11 Brown adipocytes—regulation of fatty acid oxidation and heat production 5 Muscle—acute regulation of fatty acid oxidation 12 Insulin resistance and type 2 diabetes— a response to overnutrition? 6 Muscle—long-term adaptation to exercise 13 Concluding remarks 7 Liver—acute regulation of carbohydrate metabolism References Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006031 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a006031 1 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press D.G. Hardie 1 INTRODUCTION our main focus will be the signaling pathways by which tar- get cells respond to these agents. Heterotrophic organisms, including mammals, gain en- ergy from the ingestion and breakdown (catabolism) of re- duced carbon compounds, mainly carbohydrates, fats, and 2.1 The Hypothalamus and Pituitary Gland proteins. A large proportion of the energy released, rather The hypothalamus is a small region at the base of the brain than appearing simply as heat, is used to convert ADP that controls critical functions such as body temperature, and inorganic phosphate (Pi) into ATP. The high intracel- thirst, hunger, and circadian rhythms. It modulates feed- lular ratio of ATP to ADP thus created is analogous to the ing behavior by producing neuropeptides that promote fully charged state of a rechargeable battery, representing or repress appetite. The hypothalamus also produces “re- a store of energy that can be used to drive energy-requiring leasing hormones” (e.g., corticotrophin-releasing hormone processes, including the anabolic pathways required for [CRH] and thyrotropin-releasing hormone [TRH]) that cell maintenance and growth. Individual cells must con- travel the short distance to the neighboring pituitary gland. stantly adjust their rates of nutrient uptake and catabolism Here they trigger release of peptide hormones (e.g., adre- to balance their rate of ATP consumption, so that they can nocorticotrophic hormone [ACTH] and thyroid-stimulat- maintain a constant high ratio of ATP to ADP. The main ing hormone [TSH], released in response to CRH and control mechanism used to achieve this energy homeosta- TRH, respectively). sis is AMP-activated protein kinase (AMPK) (see Box 1) (Hardie 2011). One potential problem for heterotrophic organisms is 2.2 The Adrenal Gland that there may be prolonged periods when food is not avail- The adrenal gland contains two distinct regions: a central able. They must therefore store molecules like glucose and medulla and an outer cortex. The medulla contains mod- fatty acids during “times of plenty” to act as reserves for use ified sympathetic neurons that release epinephrine (a cat- during periods of fasting or starvation. In multicellular echolamine also known as adrenaline, formed by oxidation organisms, much of this energy storage function has been and deamination of the amino acid tyrosine) into the devolved to specialized cells. For example, although all bloodstream. The hypothalamus has projections that con- mammalian cells (with the possible exception of neurons) nect with sympathetic nerves and can thus trigger epi- can store some glucose in the form of glycogen, large quan- nephrine release. For example, this occurs when blood tities are stored only in muscle and the liver. Similarly, most glucose levels drop, a response that appears to involve acti- mammalian cells can store fatty acids in the form of trigly- vation of AMPK in glucose-sensitive neurons within the ceride droplets in the cytoplasm, but storing large amounts hypothalamus (McCrimmon et al. 2008). Release of epi- appears to be harmful to many cells (see Insulin Resistance nephrine also occurs during exercise and other stressful sit- and Type 2 Diabetes section, below). Adipocytes in white uations and triggers the “fight or flight response.” As well as adipose tissue have therefore become specialized for trigly- altering blood flow via effects on the heart and vasculature, ceride storage, releasing fatty acids when other tissues need epinephrine has many metabolic effects, acting via G-pro- them. In this article, we examine the signaling pathways tein-coupled receptors (GPCRs) to increase intracellular that coordinatecarbohydrateandlipidmetabolismbetween cyclic AMP or calcium (Heldin 2012). In muscle, it stimu- energy-utilizing tissues such as muscle, energy-storing tis- lates glycogen and triglyceride breakdown, providing fuels suessuchasadiposetissue,andtheliver(anorgan thatcoor- for accelerated ATPproduction. In the liver, it promotes re- dinates whole body metabolism). lease of glucose from glycogen into the bloodstream. In adi- pose tissue, it mobilizes triglyceride stores, the fatty acids derived either being used as catabolic fuels or, in brown adi- 2 MAINTAINING ENERGY HOMEOSTASIS— pose tissue, to generate heat. HORMONES AND ADIPOKINES The adrenal cortex releases the glucocorticoid cortisol, The development of multicellular organisms during eu- which (like other steroid hormones) is synthesized from karyotic evolution required the acquisition of systems of cholesterol. This also occurs in response to starvation or hormonal and neuronal signaling that allowed tissues to stressful conditions, but in this case is triggered by release communicate their needs to each other. In this section, of ACTH from the pituitary gland. Acting via nuclear re- the critical endocrine glands and nerve centers involved ceptors that directly regulate transcription, glucocorticoids in regulation of whole body energy homeostasis, and the promote gluconeogenesis in the liver, protein breakdown in hormones and cytokines they produce, are briefly dis- muscle, and triglyceride breakdown in adipose tissue, while cussed; they are also summarized in Fig. 1. Subsequently, reducing insulin-stimulated glucose uptake by muscle. 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a006031 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Organismal Carbohydrate and Lipid Homeostasis BOX 1. THE ENERGY CHARGE HYPOTHESIS AND ENERGY SENSING BY AMP-ACTIVATED PROTEIN KINASE Catabolism generates ATPfrom ADP,whereas anabolism and most other cellular processes, such as the action of motor proteins or membrane pumps, require energyand is usually driven by hydrolysis of ATPto ADP.There is no reason a priori why these opposing processes should automatically remain in balance, and the fact that cellular ATP:ADP ratios are usually rather constant indicates that there are systems inside cells that maintain energy balance. Daniel Atkinson proposed in his energy charge hypothesis that the major signals that regulate cellular energy homeostasis would be ATP, ADP, and AMP (Ramaiah et al. 1964). AMP, like ADP, is a good indicator of energy stress, because its concentration increases as the ADP:ATP ratio increases, owing to dis- placement of the near-equilibrium reaction catalyzed byadenylate kinase (2ADP ↔ ATP + AMP). Atkinson’s hypothesis was based on findings that two enzymes, glycogen phosphorylase and phosphofructokinase, which catalyze key control points in glycogen breakdown and glycolysis (see main text), are activated by AMPand inhibited by ATP.The discoveryof the AMP-activated protein kinase (AMPK) revitalized this concept. Regulation of AMPK by adenine nucleotides is surprisingly complex (Hardie et al. 2011), but provides great flexibility. ATP 1 ADP 1 AMPK AMPK ATP:ATP ADP:ATP ATP ADP ATP Pi LKB1 PPase ADP H20 ATP ATP ADP AMP AMPK P AMPK P AMPK P ATP:ATP ADP:AMP ATP ADP:ATP ATP 100 ADP 100 AMP 1000 In the diagram above, the numerals below each form