These are notes from lecture 11 of Harvard Extension’s biochemistry class.

metabolic profiles of organs

The liver:

  • carbohydrates. The liver acts as a blood glucose buffer, takes up and releases glucose into the blood via GLUT2. G6P in the liver has three fates: glycogen production, glycolysis or the pentose phosphate pathway. The liver creates glucose from glycogen breakdown and gluconeogenesis.
  • lipids. When fuel supplies are ample, the liver synthesizes fatty acids. It releases fatty acids it has synthesized or that have been liberated from adipose tissue as VLDLs. During starvation, it converts fatty acids to ketone bodies.
  • amino acids. The liver absorbs most of the dietary amino acids. It can either synthesize proteins or catabolize amino acids depending on metabolic needs. It runs the urea cycle when needed to remove nitrogen.

The brain:

  • Very active respiratory metabolism: ~20% of the body’s total oxygen consumption and ~60% of our daily intake of glucose, used primarily to maintain the Na+ / K+ gradient across neuronal membranes. The brain cannot store glycogen. It also cannot use fatty acids as fuels, since albumin can’t cross the blood brain barrier. It can switch to ketone bodies when necessary to minimize protein degradation.


  • Can use fatty acids, glucose, and ketone bodies as fuel.  It has large glycogen stores but uses them solely for itself, never exports (it lacks glucose 6 phosphatase unlike the liver).
  • Muscle can be divided into restingmoderately active and active.  Resting muscle mostly uses fatty acids as fuel. Moderately active muscle uses glucose from glycogen as well as fatty acids. Active muscle runs glycolysis at a rate exceeding the rate of the CAC, resulting in lactate buildup. Lactate is later converted back to glucose in the Cori Cycle.
  • The muscle produces a lot of alanine through transamination of pyruvate. See alanine-glucose cycle.
  • During active exercise, pre-existing ATP stores are gone within 5 seconds.  Then phosphocreatine kicks in and can last 10-15 seconds. Then anaerobic metabolism kicks in for 45-80 seconds, converting pyruvate to lactate. However this drops the pH in the muscle and is therefore unsustainable – why you can’t sprint for a long time. After ~80 seconds, you go to aerobic exercise, in which you’re generating ATP using the ETC, which is slow but efficient.


  • Almost exclusively aerobic, with a high density of mitochondria. Fatty acids are the primary fuel source but they can also use glucose, ketone bodies and lactate.


  • It filters urea for excretion and performs gluconeogenesis.


  • When fuel is ample, stores fatty acids as TAGs from VLDL and chlyomicrons.
  • When demand for fuel increases, hormone-sensitive lipases (activated by glucagon and epinephrine) mobilize fatty acids.
  • Is also an important endocrine organ – more on this later.


  • The pancreas contains “islets of langerhans“.  Each one contains alpha cells which produce glucagon and beta cells which produce insulin.

endocrine control

Insulin (from pancreatic beta cells):

  • In the liver, stimulates glycolysis and glycogen synthesis and fatty acid synthesis.
  • In the muscle, stimulates glucose uptake (GLUT4), glycolysis and glycogen synthesis.
  • In adipose tissue, stimulates glucose uptake (GLUT4), and suppresses lipolysis.

Glucagon (from pancreatic alpha cells):

  • In liver, stimulates glycogen breakdown, gluconeogenesis, inhibits glycolysis and (after several days, eventually) stimulates ketogenesis (generation of ketone bodies).
  • In adipose, stimulates lipolysis and fatty acid mobilization
  • Muscle does not have glucagon receptors and is not affected.

Epinephrine (from adrenal glands during stress):

  • Goal is to mobilize energy reserves quickly to react to a threat.
  • In liver, stimulates glycogen breakdown and stimulates gluconeogenesis.
  • In muscle, stimulates glycogen breakdown and stimulates glycolysis.
  • In adipose, stimulates lipolysis and fatty acid mobilization.
  • In the pancreas, stimulates glucagon secretion and inhibits insulin secretion.

Other important sensors of the cellular energy state are AMP-dependent kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs).

AMP-dependent kinase is activated by AMP and inhibited by ATP. When active, it turns off ATP-consuming anabolic pathways and turns on ATP-generating catabolic pathways. Through phosphorylation of other enzymes, it activates the hypothalamus to make you feel hungry. It increases fatty acid oxidation and glucose uptake in skeletal muscle and the heart. It reduces fatty acid synthesis and gluconeogenesis and increases fatty acid oxidation in the liver. Counterintuitively, it inhibits TAG breakdown in adipose tissue – the reason for this is not known.

AMPK’s targets include fatty acid synthase, acetyl-CoA carboxylase, hormone sensitive lipase, HMG-CoA reductase, glycogen synthase.

PPAR is a nuclear receptor. It’s intracellular and, when bound by specific ligands, travels to the nucleus to act as a transcription factor. It has two domains: a ligand-binding domain and a DNA-binding domain. PPARs are lipid sensors – their ligands can be fatty acids or derivatives thereof. When bound it forms a complex with RXR (another nuclear receptor) before binding DNA.

PPARα represents the “starvation response.” It increases fatty acid oxidation, ketogenesis in the liver and increases fatty acid oxidation in muscle.

PPARγ is the “master regulator of adipogenesis.” It increase fat synthesis and storage in the liver and increases the insulin sensitivity of muscle, and increases fat uptake and storage in adipocytes. Importantly, it promotes adipocyte differentiation and survival, i.e. it creates more capacity for storage of fats. Because it increases insulin sensitivity, PPARγ is considered a drug target in diabetes research.

PPARδ senses dietary lipid and promotes fat oxidation in muscle and adipose and increases energy expenditure via thermogenesis, in adipose tissue.

PPARα and PPARδ both turn on β-oxidation genes to promote fatty acid oxidation. However they do this under different circumstances. PPARα does this in liver and muscle when the body is in starvation mode. PPARδ does this in adipose and muscle when fat stores are high.

With regards to thermogenesis, consider that uncoupling not only applies to glucose metabolism but also fatty acid metabolism – it allows fatty acids to be burned for heat. So activating uncoupling proteins increases fatty acid oxidation.

We now know that brown fat exists in adults [Cypess 2009]. Cypess detected this through FDG-PET with computed tomography (FDG-PET-CT) – the areas with high glucose uptake were brown fat. About 7.5% of women and 3.1% of men had any brown fat. Women’s brown fat was also more likely to be “active.” Brown fat was depleted in people with high BMI, which at first seems counterintuitive, but the explanation was that perhaps thin people have more need for brown fat to keep them warm.

Other researchers found that adults have progenitor cells capable of differentiating to brown adipose tissue under the right conditions [Crisan 2008]. They then used cells from obese diabetic patients and found that when patients had been treated with rosiglitazone (a PPAR agonist) for 8 weeks, UCP expression was increased, suggesting the brown adipose tissue had been encouraged. Researchers are now working on autologous stem cell transplantation with in vitro differentiation into brown adipose tissue.

The “set point” theory of body weight holds that each person has a control system specifying how much fat they should carry. The evidence for this is from rodent studies, where people have starved or force-fed rodents and then let them go back to ad libitum feeding. Rodents tend to always return to their original weight. For this theory to be true requires that there be sensors to provide information and a regulator to act on the information.

The hypothalamus acts as a the “regulator” of energy balance. The lateral hypothalamus is called the “hunger center”. This has been confirmed through lesioning studies – when the lateral hypothalamus of an animal is lesioned, they lose appetite.

Adipose tissue acts as the “sensor”. It produces peptide hormones called adipokines. These send signals to the brain about the amount of fat in the adipose tissue. Leptin is an important adipokine which is released in response to increased adipose mass. It travels through the bloodstream to act on leptin receptors in the hypothalamus. The information conveyed is “fat reserves are sufficient.” The brain then releases α-MSH, which is the “neuronal signal to eat less.” It inhibits the release of neuropeptide Y, which is the “neuronal signal to eat more.” Leptin also promotes an increase in energy expenditure through increased blood pressure and heart rate. Homozygous leptin deficient mice (called ob/ob mice) chronically overeat and become preposterously obese (they have high levels of neuropeptide Y). If injected with exogenous leptin, they will (1) decrease their hunger and food intake, and also (2) increase their energy expenditure. Homozygous leptin receptor knockout mice (db/db mice) cannot be treated with leptin, as you’d expect.

Why hasn’t leptin been used as a treatment for humans? Human obesity is associated with leptin resistance. Obese people do produce a lot of leptin but they don’t respond to it. The mechanism of resistance is a current area of research.

Parabiosis is suturing two animals together so that they end up sharing a bloodstream. When people have stiched OB/OB (leptin-producing) mice to ob/ob (leptin-deficient) mice, the ob/ob mice revert to normal weight while the OB/OB mice stay normal. (What was the point of this experiment?)

Another adipokine is adiponectin. Adiponectin is at a steady, very high concentration in your blood under all normal conditions. It increases the rate of fatty acid oxidation in muscle, reduces fatty acid synthesis and gluconeogenesis in the liver and increases glucose uptake and catabolism in muscle and liver. Its effects are indirect – it acts through AMPK. AMPK itself is cell-autonomous in its effects (?) but adiponectin allows for systemic regulation of AMPK-regulated pathways.

Through AMPK, adiponectin promotes insulin sensitization. Mice deficient for adiponectin have insulin resistance and a phenotype very similar to type II diabetes.

In obese individuals, leptin levels are higher and adiponectin levels are lower. Very low levels of adiponectin (hypoadiponectinemia) are associated with T2D.

Ghrelin is a peptide hormone produced in the stomach lining cells. It peaks before a meal and drops after, and acts on the hypothalamus. Ghrelin is exceptionally high in Prader-Willi syndrome.

PYY (peptide tyrosine tyrosine) is a peptide hormone produced by endocrine cells lining the small intestines. It is an appetite suppressant that peaks after a meal and acts on the hypothalamus.

Neurons that suppress appetite are called anorexic neurons, appetite stimuating ones are called orexinergic neurons.

overview of systemic regulation

Important points:

During an overnight fast, a few things happen:

  1. The liver breaks down glycogen and releases glucose
  2. Adipose tissue releases fatty acids
  3. Muscle and liver shift to using more fatty acids for energy to allow the brain to keep using glucose