Metabolic integration

What are the biochemical roles of the major tissues in metabolic fuel use?

• The term energy balance relates energy input to energy expenditure in the whole organism. Positive and negative energy imbalances are determined by the energy content of the metabolic fuels ingested compared with the amount of energy expended through chemical reactions, physical exertion, and thermogenic processes.

• The liver is the metabolic hub of the human body, functioning as a physiologic glucose regulator to maintain safe blood glucose levels of ~4.4 mM. The liver removes excess glucose from the blood when carbohydrate levels are high (glucose influx) and releases glucose from stored glycogen or as a product of gluconeogenesis when blood glucose levels are low (glucose efflux).

• Glucose-6-P is converted into four major products by liver enzymes: (1) glucose for release into the blood, (2) glucose-1-P for use in glycogen synthesis, (3) 6-phosphogluconolactone to generate NADPH by the pentose phosphate pathway, and (4) fructose-6-P, which is used in the glycolytic pathway to produce pyruvate.

• The human body contains two types of muscle tissue: (1) skeletal muscle, which uses different amounts of free fatty acids, glucose, or ketone bodies for metabolic fuel, depending on the physical movements; and (2) cardiac muscle, which uses fatty acids and ketone bodies as metabolic fuel to sustain a steady heartbeat.

• Adipose tissue functions as a fat depot that stores and releases fatty acids from adipocytes in response to metabolic needs. It also serves as an endocrine organ that secretes peptide hormones called adipokines to regulate metabolic homeostasis.

• Fat stored in adipose tissue consists of two basic types: (1) subcutaneous fat, which is located just below the skin surface in the thighs, buttocks, arms, and face; and (2) visceral fat, which lies deep within the abdominal cavity and is known to secrete a variety of adipokines.

• The brain is the neuronal control center of the human body. Glucose is delivered to brain cells by microcapillaries that are surrounded by cells called astrocytes, which functionally define the blood–brain barrier.

• Humans have two kidneys that are capable of filtering 6 L of human blood up to 30 times each day and removing 2 L of water containing concentrated levels of urea, NH₄⁺, ketone bodies, and other soluble metabolites. The kidneys return glucose contained in the tubule lumen to the blood by using the SGLT and GLUT transport proteins.

How do energy conversion reactions maintain metabolic homeostasis?

• Metabolic homeostasis is the process of maintaining optimal metabolite concentrations and managing chemical energy reserves in tissues. Metabolic homeostasis is regulated by physiologic inputs in response to fluctuating nutrient levels in the blood and by neuronal inputs to the brain in response to environmental changes.

• The triacylglycerol cycle is an interorgan process that continually circulates fatty acids and triacylglycerols between adipose tissue and the liver to maintain energy-rich fatty acids in circulation so that they can be used by peripheral tissues.

• When blood glucose levels are low, glycerol is synthesized from the carbon backbones of amino acids and lactate, which are used to generate pyruvate that is then metabolized by the glyceroneogenic pathway.

How do insulin and glucagon coordinate physiological fuel metabolism?

• Insulin signals high serum glucose levels, which stimulates glucose uptake, activates glycogen and fatty acid synthesis, and decreases appetite through neuronal signaling in the brain. In contrast, glucagon signals low serum glucose levels, which stimulates gluconeogenesis, glycogen degradation, and fatty acid export from adipose tissue.

• Insulin and glucagon are synthesized as prohormones in regions of the pancreas called the islets of Langerhans. The β cells secrete insulin, the α cells secrete glucagon, and the δ cells secrete somatostatin.

• Insulin signaling in liver, skeletal muscle, and adipose tissue stimulates glucose uptake and glycogen and lipid storage, whereas insulin signaling in the brain stimulates the anorexigenic neurons that decrease appetite and increase energy expenditure.

• Glucagon signaling in the liver and adipose tissue stimulates glycogen and triacylglycerol degradation. Skeletal muscle and brain cells do not express glucagon receptors.

• The human body adapts to starvation conditions by altering the flux of metabolites between various tissues with the primary metabolic objective being to supply the brain with glucose to maintain ATP-dependent ion pumps and ensure normal neuronal cell functions.

• The four major changes in metabolic flux under starvation conditions are (1) increased triacylglycerol hydrolysis in adipose tissue, (2) increased gluconeogenesis in liver and kidney cells, (3) increased ketogenesis in liver cells, and (4) protein degradation in skeletal muscle.

How do neuropeptides in the brain regulate appetite and energy balance?

• The thrifty gene hypothesis states that humans contain metabolic gene variants that provide protection against famine by maximizing fat storage during times of feast. These same gene variants contribute to the epidemic of obesity in countries where high-Calorie food is readily available.

• Mouse genetics led to the discovery of the leptin gene in obese (ob/ob) mice and the leptin receptor gene in diabetic (db/db) mice. Leptin is an adipokine hormone synthesized in adipose tissue at levels proportional to the amount of stored fat. Most obese humans have normal leptin signaling, unlike the OB and DB mice.

• Leptin circulates throughout the body and activates signal transduction in a variety of tissues, including the hypothalamus region of the brain. Activation of leptin receptors decreases appetite and increases energy expenditure to reduce lipid stores.

• Leptin (and insulin) bind to first-order POMC and NPY/AGRP neurons that produce neuropeptides (α-MSH, NPY, and AGRP), which bind to their cognate receptors on anorexigenic (eat less, metabolize more) and orexigenic (eat more, metabolize less) second-order neurons.

• The neuropeptides ghrelin and PYY₃₋₃₆ also signal through NPY/AGRP neurons in the hypothalamus to modulate energy balance. Ghrelin is synthesized in the stomach and sends signals to the brain that it is time to eat. PYY₃₋₃₆ is synthesized in the colon and counters the effect of ghrelin by sending signals that it is time to stop eating.

• Glucagon-like peptide 1 (GLP-1) is synthesized in the intestine and binds to GLP-1 receptors in POMC neurons to stimulate α-MSH secretion, which activates anorexigenic neurons to signal decreased appetite and increased energy expenditure; GLP-1 signaling decreases the rate of gastric emptying, leading to satiation.

What is the relationship between insulin resistance, obesity, and Type 2 diabetes?

• Insulin-resistant type 2 diabetes is characterized at initial diagnosis by high levels of circulating insulin and desensitization of insulin receptor signaling in muscle, liver, and adipose tissue. In contrast, type 1 diabetes is due to insufficient insulin production by the pancreatic β cells and is treatable with insulin injections.

• Unlike individuals with normal insulin signaling, those with type 1 or type 2 diabetes are unable to lower blood glucose levels within 2 hours. People with type 1 or type 2 diabetes can be distinguished by an insulin sensitivity test, which shows a decrease in blood glucose levels for those with type 1 diabetes but not for those with type 2 diabetes.

• The biochemical basis for a causal link between obesity and type 2 diabetes is complex; however, two phenotypes in individuals with obesity are strongly associated with insulin-resistant type 2 diabetes: (1) elevated levels of free fatty acids in the serum, and (2) altered secretion of peptide hormones from adipose tissue.

• Elevated fatty acids in the serum of persons with obesity leads to insulin resistance in muscle cells through production of diacylglycerol, which stimulates protein kinase C signaling. Serine phosphorylation of insulin receptor substrate 1 by protein kinase C inhibits the normal phosphorylation of insulin receptor substrate 1 tyrosine residues by the insulin receptor.

• Elevated expression of the inflammatory cytokine TNF-α in adipocytes leads to autocrine-mediated down-regulation of fatty acid metabolism genes in adipocytes and inhibition of insulin receptor substrate signaling in muscle, liver, and adipocytes.

• Not all individuals with obesity develop type 2 diabetes, and moreover, not all individuals with type 2 diabetes are overweight or obese. This suggests the link between obesity and type 2 diabetes likely involves metabolic gene variants that contribute to an elevated risk of developing insulin resistance.

• Four major classes of drugs have been developed to treat type 2 diabetes: (1) α-glucosidase inhibitors (miglitol), (2) sulfonylurea drugs that inhibit the pancreatic ATP-dependent K⁺ channel (glipizide), (3) drugs that stimulate the activity of AMPK (metformin), and (4) peptide hormones that modulate appetite, glucose metabolism, and insulin sensitivity, such as GLP-1 and glucose-dependent insulinotropic peptide (GIP).

How do nutrition and exercise affect metabolic homeostasis?

• Three factors that affect metabolic homeostasis are genetic inheritance, nutrition, and exercise. Energy balance determines body weight; however, not all foods of equal Calories provide the same nutritional value.

• In addition to the GLP-1 agonists that have been developed to induce weight loss, three other classes of compounds have been used as weight-loss drugs: (1) ephedrine is a stimulant that increases basal metabolic rates, (2) orlistat inhibits the activity of pancreatic lipase in the small intestine, and (3) olestra is a zero-Calorie food substitute containing fatty acid side chains covalently linked to sucrose.

• Consuming high amounts of saturated fatty acids and trans fatty acids on a regular basis increases LDL levels in the blood, which is associated with a higher risk of cardiovascular disease.

• The glycemic index of foods is a numerical value indicating how quickly glucose is released into the blood after eating different types of carbohydrate-containing foods. Carbohydrates with a low glycemic index cause only moderate increases in blood glucose levels over several hours.

• Exercise-induced activation of AMPK signaling alters metabolic flux through energy conversion pathways to increase ATP production in skeletal muscle cells. AMPK is a heterotrimeric serine/threonine kinase consisting of a catalytic α subunit, a regulatory γ subunit that binds AMP, and the β subunit, which functions as a molecular scaffold.

• AMPK-mediated phosphorylation of serine or threonine residues on metabolic target proteins in muscle cells leads to a net increase in ATP concentration by three mechanisms: (1) stimulation of flux through glycolysis, (2) stimulation of flux through fatty acid oxidation, and (3) increased oxidative phosphorylation.