‘Peripuberty’ is a phase in which every person’s body undergoes when childhood ends, and adolescence begins. In this phase, every individual goes through developmental changes in fat tissues and the brain.
Exposure to stress can reprogramme both changes and has long-lasting changes in the size of fat cells (adipocytes), size and composition, and social behavior.
A new study by EPFL scientists investigates the molecular mechanisms whereby the increase in adiposity induced by peripubertal stress triggers long-lasting changes in social behavior. Previous studies have shown this connection, but there has been little in identifying a biological link between the increase of adipose tissue seen in peripuberty and social impairment.
Scientists in this study found a biological connection. It explains why there is an increased predisposition to develop obesity and being less sociable in individuals that have experienced stress during early puberty.
They found that stress during the peripubertal period leads to an increase in adipose tissue in the individual’s body. In addition, they uncovered: 1. Peripubertal pressure can increase adipose tissue and reduce sociability at the same time. 2. How the two changes phenomena are biologically related.
Scientists determine if alterations in stress-induced fat composition could prompt changes in the brain that, ultimately, would cause alterations in social behavior in a protracted manner.
For this study, the mice model was used to study peripubertal stress. Scientists exposed mice to chronic, unpredictable stress. An analysis of their body composition revealed an overall increase in fat mass and larger adipocytes.
Scientists later tested mice on social tasks. They showed a life-long decrease in sociability as their adipose tissue increased. The strange fact was that female mice showed no such effect.
Is there a sex-dependent difference in other psychobiological adaptations? This remains unclear, and scientists are planning to study it in the future.
Professor Carmen Sandi at EPFL said, “What we focused here was in the reduction in sociability that you see in depression. We also know from epidemiological studies in humans that it can be linked with early life stress – peripubertal stress, which can program people to be less sociable.”
Later, scientists determined the biology behind this by pointing a series of tests to a specific enzyme called adipokine nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT is involved in some pathological metabolic problems caused by obesity.
NAMPT exists in two forms:
- An intracellular form, which regulates the production of nicotinamide adenine dinucleotide (NAD+).
- In its extracellular form (eNAMPT), the enzyme is present in the blood.
Stress during peripuberty reduces NAMPT in fat cells. Consequently, this drops eNAMPT in their blood at adulthood compared to non-stressed mice.
When scientists observed the nucleus accumbens of the socially impaired and healthy, “control” mice, they found lower NAD+ levels and problems with the enzyme Sirtuin-1. Sirtuin-1 is an enzyme that depends on NAD+ to regulate the expression of genes involved in helping the cell regulate itself in response to stressors.
Sandi said, “Since peripubertally stressed mice had lower NAD+, we assessed whether the effects we saw in sociability involved the actions of Sirtuin-1. Using multiple approaches, we demonstrated that this is indeed the case, meaning that peripubertal stress leads to protracted changes at multiple levels that link fat with brain function and behavior.”
“Peripubertal stress leads to reduced levels of NAMPT in adipose tissue and eNAMPT in blood. The latter was related to a reduction in NAD+ in the nucleus accumbens where we found reduced NAD-dependent activity of Sirtuin-1.”
The group found that this impairment affects the function of medium spiny neurons from the nucleus accumbens and ultimately promotes a reduction in sociability.
Scientists wanted to see if they could help protect against the impact of peripubertal stress in the mice. To do so, they tried: 1. bringing blood levels of eNAMPT back to normal. 2. feeding the mice with nicotinamide mononucleotide (NMN), an NAD+ booster.
Both approaches found to work: It prevents both sociability impairments and alterations in nucleus accumbens neuronal excitability.
- Laia Morato, Simone Astori et al. eNAMPT actions through nucleus accumbens NAD+/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress. Science Advances 02 March 2022. DOI: 10.1126/sciadv.abj9109