Metabolic Integration 1:Metabolic profiles of major organs, signaling and homeostasis, adaptations to starvation

Bioc 460 Spring 2008 - Lecture 40 (Miesfeld)

Eicosapentaenoic acid (EPA) is an

omega-3 fatty acid that stimulates PPAR activity

Visceral fat (apple shape) is associated with a higher risk of

cardiovascular disease than subcutaneous fat (pear shape)

Insulin hormone is a key regulator of glucose

homeostasis and is produced by pancreatic cells

• Metabolic homeostasis is a physiological state in which metabolite levels are maintained by regulatory systems acting on multiple tissues in the organism.

• The liver is the central processing facility and metabolic hub in the human body.

• Adipose tissue is not only a energy storage depot, but it is also an endocrine organ that plays a major role in controlling fatty acid homeostasis.

• Metabolic adaptations to starvation are an increase in gluconeogenesis and a switch to dependency on fatty acids as the major energy source.

Key Concepts in Metabolic Integration

Metabolic Profiles of Major Organs

What biochemical mechanisms determine G6P flux through these pathways?

Metabolic functions of skeletal muscle

During the resting state, skeletal muscle primarily uses fatty acids released from adipose tissue as a source of energy. However, when muscle contraction is required for a very short burst of activity, the exercising muscles make use of the intracellular ATP pool.

Metabolic functions of skeletal muscle

The ATP pool is replenished with ATP made by a phosphoryl transfer reaction using phosphocreatine. The creatine kinase reaction is readily reversible.

Support muscle contraction

Metabolic functions of adipose tissue

Adipose tissue was once thought of as a simple fat depot in the body that stores and releases fatty acids from adipocytes (fat cells) in response to metabolic needs. It is now known to be an active player in metabolic integration serving as an endocrine organ that secretes peptide hormones called adipokines (adipocyte hormones).

Subcutaneous Visceral

Metabolic functions of adipose tissue

One way to predict if someone has too much body fat is to determine their body mass index (BMI) using a ratio of their weight and height.

Body Mass Index (BMI) = weight (kg)/[height (m)]2

Skinny Nice Chunky

Chubby

Metabolic functions of adipose tissue

Metabolic functions of adipose tissue

Adipose tissue is responsible for regulating the triacylglycerol cycle which is an inter-organ process that continuously circulates fatty acids and triacylglycerols between adipose tissue and liver.

What might be the metabolic logic of maintaining circulating fatty acids even though 75% of it is returned to the adipose tissue and stored?

Metabolic functions of the brain

The brain is the control center of our bodies, consisting of 100 billion nerve cells (neurons) that transmit electrical information.

Left brain is the time to go to work center, the right brain is the time to party center. Blood glucose is distributed to

neurons through microcapillaries.

Metabolic functions of the brain

The brain requires as much as 120 grams of glucose each day which accounts for 60% of the glucose used by our bodies.

The brain, unlike most other organs, is exclusively dependent on glucose under normal conditions to provide chemical energy for ATP production.

High rates of glucose metabolism is indicative of neuronal activity

A liver-centric view of human metabolism

What are the two metabolic fuels exported by the liver?

Metabolic homeostasis and signaling

Metabolic homeostasis describes steady-state conditions in the body and can apply to a wide variety of physiological parameters.

Regulation of metabolic homeostasis requires both neuronal signaling from the brain and the release of small molecules into the blood that function as ligands for receptor-mediated cell signaling.

Population homeostasis

Physiological homeostasis

Physical homeostasis

Insulin and Glucagon Signaling

Two of the most important global metabolic regulators in humans are the peptide hormones insulin and glucagon, both of which are secreted by the pancreas. Insulin and glucagon are synthesized as prohormones in a region of the pancreas called the islets of Langerhans. They are the yin and yang of glucose homeostasis.

Insulin and Glucagon Signaling

Glucagon circulates through the body,why “no effect” in muscle and brain tissue?

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Peroxisome-proliferator activated receptors (PPAR) are recently discovered metabolic regulators

Discovered in the early 1990s, the PPAR, PPAR and PPAR nuclear receptor proteins are now known to be key players in controlling metabolic homeostasis in humans.

PPARs function as transcription factors that regulate gene expression in response to the binding of low affinity fatty-acid derived nutrients such as polyunsaturated fatty acids and eicosanoids.

This property of PPARs makes them ideal metabolic sensors of lipid homeostasis and results in long term control of pathway flux by directly altering the steady-state levels of key proteins.

PPARs are lipid-activated transcription factors

One of the most important functions of PPAR is to control adipocyte differentiation and lipid synthesis in adipose tissue, but it also regulates insulin-sensitivity in all three tissues, as well as, lipid synthesis in liver cells.

PPAR is the therapeutic target of thiazolidinediones (TZDs) which improve insulin-sensitivity in type 2 diabetics by activating PPAR target genes involved in lipid synthesis.

PPARs are pharmaceutical targets for diabetes

Diabetics who are treated with TZDs see a drop in blood glucose levels which is good, but they also gain weight.

What explains this side effect?

Gemfibrozil is a PPAR-selective fibrate currently in use to treat high cholesterol in patients, and rosiglitazone is a TZD compound that binds with high affinity to PPAR and is used to treat type 2 diabetes. The PPAR-selective agonist GW501516 has been evaluated in human clinical trials for the treatment of atherosclerosis and obesity by altering flux through lipid metabolic pathways.

PPARs are pharmaceutical targets for diabetes

PPARs are pharmaceutical targets for diabetes

The size of the ligand pocked in PPARs was confirmed by the PPAR protein structure which revealed the position of a bound agonist.

PPARs are pharmaceutical targets for diabetes

The human body adapts to these near starvation conditions by altering the flux of metabolites between various tissues in order to extend life as long as possible.

The primary metabolic challenge is to provide enough glucose for the brain to maintain neuronal cell functions; the brain cannot use fatty acids for metabolic fuel because of the blood-brain barrier.

Red blood cells (erythrocytes) are also dependent on serum glucose as a sole source of energy to generate ATP because they lack mitochondria and are not able to utilize fatty acids.

Metabolic Adaptations to Starvation

Why can’t red blood cells utilize fatty acids as an energy source?

In order to make up for the loss of liver glycogen after the first 24 hours, the body's metabolism changes in two important ways.

1) flux through the gluconeogenic pathway.

2) switch most of the energy needs to using fatty acids as the primary metabolic fuel.

The bulk of stored metabolic fuel is in the form of triacylglycerols in adipose tissue which is sufficient to prolong life for 3 months. Protein is the second most abundant stored fuel (14 days worth of energy) which is spared for as long as possible to permit mobility.

Metabolic Adaptations to Starvation

The four major adaptations are:

• Increased triacylglycerol hydrolysis in adipose tissue.

• Increased gluconeogenesis in liver and kidney cells.

• Increased ketogenesis in liver cells.

• Protein degradation in skeletal muscle tissue.