Mice stressed in early years show social behaviour deficits and excessive fat accumulation later in life.Deficiency of NAMPT in blood and adipose tissue, a NAD+-producing enzyme, is related to early-life stress and decreased sociability.Nicotinamide mononucleotide (NMN) treatment, a NAD+ booster, can stop the deterioration of brain function and sociability. Childhood obesity is known to cause several devastating health issues, including impaired social skills, which can have lasting effects on a child’s life. These interactions can trigger stress while going through puberty, influencing long-term changes in fat distribution and impacting a teenager’s emotional and mental well-being. Presently, the extent to which changes due to stress in adipose tissue communicate with the brain to drive behavioural shifts remains uncertain. A recent study published in the science journal (Science Advances) has focused on the connection between stress-induced fat increases during puberty and alterations in brain activity. A Swiss team of researchers from Ecole Polytechnique Fédérale de Lausanne (EPFL) Brain Mind Institute, delved into the enzyme NAMPT’s (responsible for NMN production) role in this process. The scientists observed that heightened fat levels stemming from puberty-related stress disrupt NAMPT’s communication between fat and the nucleus accumbens, a brain region. This part governs the pleasurable aspects of social interactions and behaviour. The team’s findings suggested that reduced NAMPT levels contribute to enduring declines in sociability resulting from peripubertal stress. Remarkably, administering NMN-supplemented water, 100 mg/kg per day, counteracted these sociability impairments. It also restored proper nucleus accumbens neuron function. These results highlight the benefits of NMN and similar NAD+-fortifying compounds to mitigate the lasting effects of stress in early years on social behaviour and its correlation with heightened fat levels. Social Interaction and Obesity Interpersonal relationships significantly influence both individual and societal well-being. Impaired sociability, characterised by social withdrawal or avoidance, often signifies various mental health conditions. Previous research has linked childhood and adolescent stress exposure to heightened fat accumulation and obesity, coupled with reduced sociability. Dr Carmen Sandi, the senior author of the study says stress can cause psychopathologies like depression. Symptoms like sociability alterations are also common; individuals become withdrawn or socially avoidant, with some developing social anxiety. Puberty-Stressed Adult Mice and NMN Benefits Examining the connection between sociability deficits and fat accumulation, Morató and his colleagues developed a mouse model, focusing on reduced sociability seen in depression. Human epidemiological studies clarify fat deposition may be linked to stress during puberty. This can predispose individuals to become less social as adults. The model explored whether changes in early-life stress-induced fat accumulation could cause alterations in the brain, ultimately leading to changes in behaviour. In their study, mice underwent stress in puberty, leading to reduced muscle mass, rise in fat mass, glucose intolerance, diminished muscle energy and enlarged adipocytes in adulthood. This suggested peripubertal stress redirects adult metabolism towards energy accumulation in adipose tissue, putting the metabolism at risk. Stress During Puberty, NMN Supplementation and NAD+ Signalling The EPFL team’s research shows that puberty-stressed mice experience reduced secretion of fat-secreted compounds, including leptin and eNAMPT. Leptin, predominantly fat cell-manufactured, regulates energy balance by curbing hunger and fat storage. Adult mice subjected to peripubertal stress exhibited reduced NAD+ levels in the nucleus accumbens. These NAD+ level drops are correlated with diminished gene activity in SIRT1 targets, an enzyme linked with extended longevity. To explore this further, the researchers injected NMN, a SIRT1 modulator that boosts NAD+, into the nucleus accumbens of stressed mice. This intervention reversed the sociability deficits due to stress. Conversely, co-injection containing SIRT1 inhibitor nullified the effect, confirming SIRT1’s involvement. Further experiments showed boosting mice’s drinking water with NMN supplements benefits the body. It stabilises stress-induced NAD+ level reductions, social behaviour, and neuron activity inside the nucleus accumbens. Another experiment examined the effects of activating NAMPT in adult mice’s adipose tissue. NAMPT normalised levels of eNAMPT, nucleus accumbens NAD+ content, and behaviour following peripubertal stress. Additionally, NAMPT gene activation in adipose tissue decreased stress-induced fat accumulation and fully restored sociability. Importantly, NMN injection or SIRT1 targeting in the nucleus accumbens didn’t influence body composition, signifying the distinct purpose of NAMPT in fat cells. Boosting NAD+ Levels in Youth The study disclosed a pathway linking peripubertal stress-led fat accumulation to sociability deficits in adults. The researchers proposed NAD+ boosters as a viable strategy to counteract behavioural deficits arising from altered fat metabolism, particularly due to early-life stress. Yet, more research on boosting NAD+ during puberty is necessary before considering its application in stressed children or adolescents. Dr Sandi emphasises the importance of analysing plasma NMN or eNAMPT levels. She also suggests conducting targeted studies to assess the effectiveness of this approach in younger populations.