Leptin is Everywhere

by Ronke Odubela and Mónica Valdez

Hey, it’s the Thriving Metabolites back at again!

Our topic for this week…LEPTIN! Yeah, I know we talked about it last week but guess what? There’s more!

Just to recap, what is leptin? Leptin is a key hormone in energy homeostasis and it also regulates neuroendocrine function; including reproduction. Surprise! Leptin does more than just telling you when to eat and when not to eat; it also plays a huge role in the human reproduction system, fertility and also some disorders bb. Puberty and reproductive function largely depend on metabolic state. It is important for puberty because puberty is activated by Kiss1 neurons in the arcuate nucleus. It is theorized that leptin activates these Kiss1 neurons by activating POMC and CART; from there the kiss1 neurons stimulate release of Gnrh. Reproductive function also involves the activation of Kiss1 neurons. Leptin deficiency can also cause big problems with reproduction and puberty. One form of deficiency is called hypoleptinemia. Hypoleptinemia occurs when a lack of leptin activity results in drive to consume food and conversation of energy expenditure that does not feedback to the hypothalamus.

Another deficiency is also hypogonadism; which is complete leptin deficiency due to homozygous leptin gene mutations. Through studies this leptin deficiency has been shown to delay the onset of puberty — the gondatropin responses but there was a defect at the hypothalamic level. Although these two deficiencies highlight the fact that leptin is not just a hormone meant to regulate energy homeostasis, there is also is a third deficiency as well, that makes the connection between leptin and reproductive issues even stronger. It’s called hypothalamic amenorrhea (HA). People will HA drastically have lower leptin concentrations, hypoleptinemia. In addition to dysfunctional HPG axis, resulting in anovulation and estrogen deficiency to prevent pregnancy, there are also increased concentrations of cotricotropin releasing hormone, adrenocorticotropic hormone, cortisol, and low to normal concentrations of thyrotropin and thyroid hormones, as well as increased concentrations of growth hormone resistance. With this not only is your reproduction system completely messed up, in the end it can also lead to infertility. You can image that you are trying to a finish a puzzle so you can take a picture and show your friends your accomplishment. You have one more piece left but all of sudden you can’t find it anywhere, so now your puzzle is to forever remain unfinished and you can’t complete any of the things you wanted to do after finishing your puzzle because you are so upset. So for HA, replace the puzzle piece with leptin and the puzzle is your reproduction system. Your reproduction is missing a pivotal piece to have everything working correctly and that in the end throws everything else that has to reproduction as well. But don’t worry, there is a hero in this story…..Metreleptin! This was administered to patients with HA, and this administration lead to ovulatory menses, high level LH, estradiol, thyroid hormone, IFG1, and bone marrow formation markers. There were also positive changes in their leptin levels. Overall things were looking to go from bad to normal for these patients with HA.

It is interesting that one hormone can have so many effects on the body. Leptin deficiency can lead to more things, and one topic of conversation is type 1 diabetes. People with type 1 diabetes have lower leptin levels, and this is because it is believed to be linked to insulin deficiency. The treatments seen in the instance of this disease show that with increased leptin levels, there is improved glucose control and regulation — which is the ultimate cause of diabetes. What you may be thinking is: insulin does the same thing, isn’t that what the treatment for diabetes is? If you are thinking this, you would be in part correct, however, there’s a little more action going on behind the scenes. Even with the introduction of insulin to type 1 diabetes patients, they still experienced many signs of leptin deficiency including hypogonadism, low fertility rates, and delayed puberty. Even though it hasn’t been studied in human yets, when rats were offered leptin therapy over insulin, they had a restoration of the Kiss1 gene expression (discussed earlier) as well as sex steroid concentrations!

While learning about the mechanisms that go with leptin are interesting, what happens when patients are leptin resistant? There have been several suggested reasons why they are leptin resistant including impaired transport, signaling, and pathway malfunction. What does being leptin resistant do to the individual? Well, central leptin resistance has been tied to obesity and lower natural pregnancy rates. To counter act what was happening in the rats that were being studied, scientists were able to reverse the effect they stimulated gonadotropin, a hormone. Interestingly enough, scientists mainly saw the loss of fertility rates in females and not males. This is believed to be because there is more of an effect on the reproductive system of females than males — but studies are still being conducted to further investigate.

Truly, we could go on and on about a multitude of disorders, symptoms, and conditions that are directly affected by leptin in some way, shape, or form. We’re glad that you stuck around to hear us talk more about leptin, and we hope you stay tuned for many more exciting things to be learned in cogs 163!