Girls have been experiencing puberty earlier in life for the last 150 years or so, with 12.5 years being the average age girls start puberty today. Early-onset puberty can lead girls to experience health problems later, including increased incidence of ovarian, uterine and breast cancers, as well as being at a higher risk for cardiovascular and metabolic diseases. But the human genome – the complete set of nucleic acid sequences in human DNA – hasn’t changed substantially in the past 150 years. So Lomniczi and colleagues are now exploring if the difference might be due to epigenetics, or changes caused by gene expression rather than changes in the genetic code itself. Gene expression is when genes make functional products such as proteins. Becoming overweight at a young age can trigger a molecular chain reaction that leads some girls to experience puberty early, according to new research published in Nature Communications. Scientists have discovered a molecular mechanism that leads overweight female rats to have early-onset puberty.
“Knowing how nutrition and specific molecules play a role in starting puberty early could one day help physicians prevent the condition in humans,” said one of the study’s corresponding authors, Alejandro Lomniczi, PhD, a research assistant professor at OHSU’s Oregon National Primate Research Center. Lomniczi’s previous research identified two gene families that keep puberty in check when rodents and nonhuman primates are young. This new study builds on that earlier work by specifically examining how gene expression and body weight are involved in puberty in rats. For this study, the team raised three kinds of female rats: overweight, lean and average-sized. While focusing on the hypothalamus, the bottom part of the brain that controls reproductive development, they found that a puberty-activating gene called Kiss1 was expressed differently in each rat type. Lomniczi and colleagues identified the enzyme SIRT1 in the hypothalamus as being a key player in transmitting body weight information to the brain.
Among sirtuins, SIRT1, with abundant expression in the brain and different metabolic peripheral tissues, is the most extensively studied. SIRT1 operates as NAD+-dependent deacetylase (enzyme), acting on histones and other cellular targets to conduct a wide array of biological functions, including epigenetic control and modulation of life/health span. Sirtuins act as bona fide cell energy sensors: activation of sirtuins is tightly coupled to changes in the availability of the metabolic cofactor, NAD+, so that conditions as caloric restriction and nutrient deprivation, which increase the NAD+/NADH or NAD+/nicotinamide ratios, result in increased SIRT1 content and activation in various tissues. Because SIRT1 is activated in the adult hypothalamus by decreased nutrient availability and is abundant in a brain region called nucleus arcuatus (ARC), the team explored the notion that SIRT1 is a key component of the epigenetic machinery that regulates the timing of puberty, by conveying nutritional information to KNDy neurons.
These group of neurons produce some neurotransmitters that drive the secretion of the GnRH hormone. This, in turn, set in motion the endocrine manifestations of puberty. In overweight rats, there is less SIRT1 in the hypothalamus, allowing the Kiss1 gene to be expressed earlier, leading the rats to undergo puberty early. In lean rats, SIRT1 is higher for a prolonged period of time, taking longer for Kiss1 gene activation, which delayed puberty in those rats. The nutritional status of an individual has strong environmental promptings, suggesting that nutrition may influence reproductive development via epigenetic mechanisms. This means that a wrong pre-puberal diet is able to change gene expression in the ARC (and maybe in other brain ares), that would set the early onset of puberty in girls. At least, this study proves that the fenomenon applies to mice “girls”. Further studies will devote more effort for translation of these result into human practice. Dr. Lomniczi continues to explore the causes of early-onset puberty through; the next step will be how the circadian clock and endocrine disruptors might play a role.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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