Between the end of childhood and the beginning of adolescence, there is a critical window of time called “peripuberty . ” This transition period involves developmental changes in both adipose tissue and the brain, where both can be reprogrammed through exposure to stress, which can lead to long-lasting changes in the size and composition of fat cells (adipocytes), as well as in the change of social behavior.
In a new study, scientists led by Professor Carmen Sandi from EPFL found that stress during the peripubertal period leads to an increase in adipose tissue in the individual’s body. Although previous studies have demonstrated this connection, there has been little in the way of identifying a biological link between the increase in adipose tissue observed in peripuberty and social decline.
The study is published in Science Advances .
“We know that stress can induce psychopathologies, including depression,” says Sandi. “Some of the characteristic behavioral changes you see in depression are alterations in the individual’s sociability, which means that some depressed people tend to be more withdrawn, a bit socially avoidant; some may even develop social anxiety.”
Stress, sociability and mice.
In the study, Sandi’s group discovers two ideas in the field:
- First, that peripubertal stress leads to an increase in adipose tissue and reduces sociability at the same time.
- Secondly, how the two change phenomena are biologically related.
“We explored whether alterations in fat composition – induced by stress in the first years of life – could be responsible for inducing changes in the brain that would ultimately cause long-term alterations in social behavior,” he says. Sandi.
To study peripubertal stress, researchers needed a model. They turned to mice , within the peripubertal age window, and exposed them to chronic, unpredictable stress. A study of their body composition revealed an overall increase in fat mass and larger adipocytes.
Upon reaching adulthood, the mice were tested on social tasks. Male mice showed a decline in lifelong sociability as their adipose tissue increased, but interestingly, females showed no such effect. But whether or not there is a sex-dependent difference in other psychobiological adaptations is something Sandi’s group will study in the future.
“What we focused on here was the reduction in sociability that you see in depression,” Sandi says. "We also know from epidemiological studies in humans, that it may be related to early life stress: peripubertal stress, which can program people to be less social."
The NAD+ Connection
The researchers then set out to identify the underlying biology. A series of tests pointed to a specific enzyme called adipokine nicotinamide phosphoribosyltransferase (NAMPT), which is known to be involved in some of the pathological metabolic problems caused by obesity.
In the body, NAMPT exists in two forms: An intracellular form, which regulates the production of nicotinamide adenine dinucleotide (NAD+), a molecule important for energy generation in the cell. In its extracellular form (eNAMPT), the enzyme is present in the blood.
Stress in the brain
The researchers found that mice that had been stressed in peripuberty showed a decrease in the amount of NAMPT in fat cells and, consequently, eNAMPT in the blood in adulthood compared to non-stressed mice.
By looking at the nucleus accumbens , a brain region that regulates motivated behaviors, in both healthy "control" and socially disabled mice, the researchers identified lower levels of NAD+ and problems with the enzyme Sirtuin-1, an enzyme which depends on NAD+ to regulate the expression of genes involved in helping the cell regulate itself in response to stressors.
"Given that peripubertally stressed mice had less NAD+, we tested whether the effects we saw on sociability involved the actions of Sirtuin-1," Sandi says. “prolonged changes at multiple levels that link fat to brain function and behavior.”
NAD+ enhancers: a solution?
“Peripubertal stress leads to reduced levels of NAMPT in adipose tissue and eNAMPT in the blood,” says Sandi. "The latter was related to a reduction in NAD+ in the nucleus accumbens, where we found reduced NAD-dependent Sirtuin-1 activity." The group found that this impairment affects the function of the medium spiny neurons of the nucleus accumbens and ultimately promotes a reduction in sociability.
Having implicated the NAD+/Sirtuin-1 pathway in the nucleus accumbens, the team sought to see if they could help protect against the impact of peripubertal stress in mice. They did this in two ways: by normalizing blood levels of eNAMPT or by feeding the mice nicotinamide mononucleotide (NMN), an NAD+ booster. Both approaches worked, preventing both deficiencies in sociability and alterations in neuronal excitability of the nucleus accumbens.
But are NAD+ boosters, which are popular in the US and EU, but not on the Swiss market, a solution to treating the social impact of stress that is increasingly seen in young people today? Sandi is cautious: “We have to be careful because we applied nutritional treatments in our study in adulthood,” she says. “We are not saying that stressed children or adolescents should take NMN; It will be important to first look at whether they have reduced plasma levels of NMN or eNAMPT, and perform specific studies to see the effectiveness of this approach for younger populations. “So what makes sense is to restore low metabolic levels, not treat everyone the same if there is no biological reason.”
