Organismal carbohydrate and lipid homeostasis

Abstract

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, multicellular eukaryotes have assigned the task of storing energy to specialized cells such as adipocytes, 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 signaling 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. Overnutrition can dysregulate these pathways and have damaging consequences, causing insulin resistance and type 2 diabetes.

Figure 1.

Summary of endocrine systems that regulate energy balance by modulating carbohydrate and lipid metabolism. Neurons in the hypothalamus promote feeding, and the successive release of corticotrophin-releasing hormone (CRH), adenocorticotrophin-releasing hormone (ACTH), and cortisol from the hypothalamus, pituitary, and adrenal cortex, respectively, and release of epinephrine from the adrenal medulla. Hypothalamic neurones are activated by low glucose, the thyroid hormone T3, and adiponectin, while being inhibited by leptin and insulin. The α and β cells in the pancreas monitor blood glucose independently, releasing glucagon and insulin, respectively. Insulin and leptin are hormones that represent nutrient surplus, whereas cortisol, epinephrine, and adiponectin are hormones that represent either deprivation of nutrients (e.g., starvation) or demand for energy (e.g., during exercise).

Figure 2.

Regulation of glycogen breakdown in skeletal muscle. Muscle contraction increases ADP and AMP and decreases ATP, activating both phosphorylase b (phos b) and phosphofructokinase (PFK) through allosteric regulation, thus promoting glycogen breakdown and glycolysis to generate ATP. However, contraction (initiated by firing of motor nerves that release acetyl choline) is triggered by release of calcium from channels in the sarcoplasmic reticulum membrane, also activating phosphorylase kinase. The latter phosphorylates phosphorylase and converts it to the a form (phos a), which no longer requires AMP for activity. Increases in cyclic AMP levels, triggered by binding of epinephrine to receptors on the plasma membrane, activate cyclic-AMP-dependent protein kinase (PKA). PKA phosphorylates phosphorylase kinase and amplifies its activation by the calcium-dependent mechanism.

Figure 3.

Regulation of muscle glucose uptake and glycogen synthesis by insulin and contraction. In resting muscle in the fed state, insulin binding to its receptor activates the PI-3-kinase → Akt pathway. Akt phosphorylates the Rab-GAP protein TBC1D4 (AS160) attached to GLUT4 storage vesicles (GSVs), causing its dissociation and promoting Rab:GTP-mediated fusion of GSVs with the plasma membrane and increased glucose uptake. This causes accumulation of glucose 6-phosphate (G6P), which activates glycogen synthase; the latter is also dephosphorylated and activated following inactivation of GSK3 by Akt. Muscle contraction, by contrast, causes increases in ADP and AMP levels that activate AMPK. AMPK phosphorylates TBC1D1, causing GSVs to fuse with the membrane. In this case, G6P does not accumulate because of the demand for ATP, and AMPK also inactivates glycogen synthase. This drives flux from increased glucose uptake into ATP production rather than glycogen synthesis.

Figure 4.

Acute regulation of glycolysis and gluconeogenesis in the liver. Reaction steps unique to glucose release via gluconeogenesis or glycogenolysis are shown in blue. The steps opposing liver pyruvate kinase (L-PK) in gluconeogenesis are not shown in detail. During fasting or starvation, epinephrine and glucagon increase calcium and cyclic AMP (cAMP) levels, activating phosphorylase kinase and cAMP-dependent protein kinase (PKA), which act together to promote glycogen breakdown. During starvation, PKA also phosphorylates L-PK and 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK2/F2BPase), inactivating the former, and inhibiting the kinase and activating the phosphatase activity of the latter. This causes a drop in fructose 2,6-bisphosphate levels, which triggers a net switch from glycolysis to gluconeogenesis.

Figure 5.

Regulation of the G6Pc promoter, showing the approximate location of elements binding the key transcription factors. Glucocorticoids such as cortisol, in complex with the glucocorticoid receptor (GR), bind to three sites within the glucocorticoid response unit, enhancing transcription. Cyclic AMP-dependent protein kinase (PKA) phosphorylates cyclic AMP response element binding protein (CREB), recruiting CREB-binding protein (CBP), and activating transcription. Finally, Akt phosphorylates FoxO at multiple sites, triggering the binding of 14-3-3 proteins and their nuclear exclusion, thus inhibiting transcription. Not shown are the roles of coactivators other than CBP described in the text, i.e., PGC-1α and CRTC2.

Figure 6.

Regulation of processing of SREBPs. The precursor forms of SREBPs bind to the membrane protein SCAP through interactions between their carboxy-terminal regulatory domain (RD) and the WD repeat domain (WDD) of SCAP. The SREBP-SCAP complex is retained in the endoplasmic reticulum by interaction with Insigs. Reduced binding of sterols to the sterol-binding domain (SBD) of Insig1 and the sterol sensor domain (SSD) of SCAP causes their dissociation, and the SCAP-SREBP2 complex then translocates to the Golgi, where the site 1 and site 2 proteases (S1P and S2P) cleave SREBP2, releasing the transcription factor domain (TFD) that translocates to the nucleus. Regulation of SREB1c is similar, except that there appears to be multiple mechanisms that trigger its release from the ER, including insulin-induced degradation of Insig2.