bone formation

Let's Leap into Leptin!

So there was a request to go more into leptin.  I mentioned a few factoids here and there but I think I can manage to do it in a more coherent manner! 

Leptin is a 16kDa protein hormone and in humans is made up of 167 amino acids.  It was discovered in 1994 via studies done with super obese mice at Rockefeller University that were not only morbidly obese but also incredibly hungry.  The mice themselves also had transient hyperglycemia (high blood sugars) and elevated plasma insulin concentrations 10-50x that of a normal mouse.  I’m not sure how that chubby mouse even walked to get to the food!

  • Da stands for Dalton which is a unit of mass for mass on an atomic or molecular scale.  1Da is ~equal to the mass of one proton or one neutron.
  • Proteins are biochemical compounds made up of amino acids that have folded up into a globular form in a biologically functional way.
  • Hormones are chemical messengers that are released by a cell or a gland in one part of the body that affect cells in other parts of the organism.

This protein hormone is mainly made in adipocytes of white adipose tissue.  Or in lay terms, it’s synthesized in the fat cells of the fatty tissue where we store excess energy.  It’s the same fatty tissue that acts as a thermal insulator and mechanical “cushion” and makes us break our new year’s resolutions.  Interestingly, levels of leptin CORRELATE with fatty tissue mass.  So the fatter you are, the higher your leptin levels probably are.  And the larger those fat cells are, the higher the levels of leptin created.

So when you eat (and this has been mentioned before), the sugars that the liver comes across triggers pancreatic cells to produce insulin.  Insulin has been found to induce leptin production in the fatty cells. [3] Note that leptin production has also been found to reduce insulin production - a bit of a feedback loop there.  Insulin secretion tracks changes of energy balance on the order of minutes to hours as opposed to days as is the case for leptin, and these changes are always in direct proportion to fatty tissue mass.  [2] This however is not the only inducer of leptin production as studies have also implicated glucocorticoids. 

So when leptin is produced - via transcription of the ob gene - it makes its way to the bloodstream and up to the brain.  In the brain it acts mainly on receptors (Ob-R) in the hypothalamus (region that controls body temperature, hunger, thirst, fatigue, sleep, and circadian cycles). [1]

  • Transcription of the ob gene for leptin receptors yield five isoforms of Ob-R: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, and Ob-Re Ob-Rb has been found to be the receptor responsible for mediating weight-reducing effects of leptin (a mutation in this receptor leads to massive obesity). [6]
  • These leptin receptors have been found in many other organs and suggest that leptin has other actions independent of the functions in the brain.  And of course, as mentioned before, there are studies that indicate that when leptin is produced, one of the places it inhibits is insulin production in the pancreas.

What Leptin actually DOES (besides weight/appetite regulation) is still being discovered.  The following are a sampling of what has been found thus far:

1) The presence of leptin reduces production of neuropeptide Y (NPY) which is a feeding stimulant made by cells in the gut and hypothalamus.  (One study administered NPY which caused the animals to have increased appetites.  And when they were given leptin, their appetites went back to normal.) [4]

2) Leptin decreases levels of insulin even with minute amounts. The studies administered insulin and dexamethasone into subjects and found significant increases in serum leptin levels.  Another one demonstrated that insulin-stimulated glucose metabolism increases the transcriptional activity of the leptin promoter (a section before the specific gene that says, go, be transcribed). This also makes you wonder that if your body is in a constant state of high leptin, does this lead to insulin not being produced and therefore hyperglycemia? [2, 5]

3) Leptin has a potential role in the immune system.  In mice with leptin deficiencies, malnourished infants, and fasting subjects - leptin levels are decreased and immune/endocrine markers of starvation increase.  When leptin signaling is deficient, there is impairment of humoral and cellular immune responses.  The leptin receptor Ob-Rb is expressed by B and T lymphocytes, suggesting that leptin regulates directly the B and T cell responses.  Administration of leptin to mice also reversed the acute immunosuppressive effects of starvation.  [7, 8] In other words, leptin is part of the immune system - potentially controlling parts of it, and a marked decrease of leptin seems to correlate with increases of markers of starvation.

4) Leptin regulates bone formation.  Studies have suggested that leptin increases bone mass and reduces bone fragility when administered peripherally but can also indirectly reduce bone mass when administered into the central nervous system.  And in the absence of leptin signaling, bone mass and strength are reduced. [9]

5) An interesting study suggests that leptin actually works by rewiring the brain and that these circuits are hardwired close to birth.  They found that in mice without the leptin gene, there were more-than-normal connections going into neurons that would have been affected by leptin.  This led to more circuits that increased appetite.  But when the mice were given leptin, those circuits reversed and the mice developed normal neural circuits with normal body weights.

Another study related to the above found that right after birth there were surges in leptin in both humans and mice which was perplexing given that leptin is supposed to be an appetite suppressant.  What they found was that in mice without the leptin gene, the neurons that normally respond to leptin failed to project to other regions of the brain involved in food intake.  When the mice were given leptin immediately after birth, all the neural circuits that control food intake formed normally and the mice maintained normal weight.  However, if the leptin-deficient mice were not given leptin until adulthood, the circuitry was not restored and the mice remained fat.

Taken together, the two studies suggest that leptin affects two distinct types of neural connections at different times. Early in life, leptin guides output from neurons that affect appetite. Later, leptin signals the input to these same neurons. [10-12]

I actually could probably go on and on about the systems that leptin has been discovered to be a part of.  There’ve been more studies that implicate leptin’s roles in reproduction, angiogenesis, and even hematopoiesis.  But as they’re all just on the forefront of discovering this, it can’t be said that 100% leptin acts in X manner.

  1. Fei, H., Okano, H.J., Li, C., Lee, G.H., Zhao, C., Darnell, R. (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues.  Neurobiology, 94:7001-7005.
  2. Considine, R.V., Sinha, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., Ohannesian, J.P., Marco, C.C., McKee, L.J., Bauer, T.L., Caro, J.F. (1996) Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans. N Engl J Med, 334:292-295.
  3. Kieffer, T.J., Habener, J.F. (2000) The adipoinsular axis: effects of leptin on pancreatic beta-cells. Am J Physiol Endocrinol Metab, 278:E1-E14.
  4. Jang, M., Mistry, A., Swick, A.G., Romsos, D.R. (2000) Leptin Rapidly Inhibits Hypothalamic Neuropeptide Y Secretion and Stimulates Corticotropin-Releasing Hormone Secretion in Adrenalectomized Mice. Journal of Nutrition, 130:2813-2820.
  5. Seufert, J. (2004) Leptin Effects on Pancreatic Beta-Cell Gene Expression and Function. Diabetes, 53(1):S152-S158.
  6. Gorska, E., Popko, K., Stelmaszczyk-Emmel, A., Ciepiela, O., Kucharska, A., Wasik, M. (2010) Leptin Receptors. Eur J Med Res, 15Suppl2:50-4.
  7. Fernandez-Riejos, P., Najib, S., Santos-Alvarez, J., Martin-Romero, C., Perez-Perez, A., Gonzalez-Yanes, C., Sanchez-Margalet, V. (2010) Role of Leptin in the Activation of Immune Cells, Mediators of Inflammation, 568343.
  8. Lord, G.M., Matarese, G., Howard, J.K., Baker, R.J., Bloom, S.R., Lechler, R.I. (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature, 394:897-901.
  9. Williams, G.A., Callon, K.E., Watson, M., Costa, J.L., Ding, Y., Dickinson, M., Wang, Y., Naot, D., Reid, I.R., Cornish, Y. (2011) J Bone Miner Res, Epub.
  10. Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110-115 (April 2, 2004).
  11. Bouret, S.G. et al. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 110-115 (April 2, 2004).
  12. Elmquist, J.K. and Flier, J.S. The fat-brain axis enters a new dimension. Science 304, (April 2, 2004).

Google Books -

Handbook of neurochemistry and molecular neurobiology: Behavioral Neurochemistry and Neuroendocrinology. [Edited by Jeff Blaustein]

Leptin [Edited by V. Daniel Castracane, Michael Chris Henson]


Study Links Regular Exercise to Strong Bones

Drinking milk isn’t the only thing you can do to promote strong and healthy bones. According to a new study, exercise can also promote strong bones.

Researchers at Tufts University School of Dental Medicine found that exercise stimulates the production of a special hormone known as irisin, and elevated levels of this hormone may offer benefits in strengthening bone density.

For the study, researchers has participants perform running wheel exercises to induce the production of irisin. At the end of the study period, researchers concluded that irisin increased bone formation and thickness in participants.

When speaking about the study, researcher Jake Chen explained that irisin is beneficial in the skeletal system. He added, however, that more research needs to be done to make any definitive statements regarding irisin and bone strength.

Our results provide insight into the complex regulatory interplay of muscle, bone and fat tissues. Increased irisin levels in circulation upon systemic administration can recapitulate part of the beneficial effects of exercise in the skeletal system,” said study author and researcher Jake Chen. “Further experimentation will be needed to evaluate the involvement of irisin and other factors increased by exercise and expressed by bone, muscle and fat tissue.”

So, what does this mean exactly? It means that exercising on a regular basis leads to increased production of the hormone irisin, which in turn promotes strong and healthy bones. Of course, there are other ways to maintain strong bones, such as consuming an adequate amount of calcium and vitamin D, as well as performing strength training exercises.

Maintaining strong bones is particularly important for older adults and seniors. Regardless of your age, however, you should make changes to your lifestyle to promote stronger bones. The tips listed above, including exercise, can help set you on the right path.

This study was published in the journal Bone Research.