High-fat diet exposure from prenatal life to early adulthood induces sex-specific neuropsychiatric vulnerability in mice

Obesity is associated with an increased risk of neuropsychiatric disorders, including depression and cognitive decline. However, the sex-specific effects of chronic exposure to an obesogenic diet remain poorly understood. Here, female mice were fed either a high-fat diet (HFD) or a control diet starting four weeks before mating and continuing throughout gestation and lactation. Their male and female offspring remained on the same diet until young adulthood. Body weight was monitored weekly, and behavioural, neurochemical and biochemical assessments were conducted at eight weeks of age. In the Splash Test, HFD increased latency and reduced grooming time in both sexes, whereas only males exhibited increased immobility in the Tail Suspension Test, indicating greater depressive-like behaviour. In addition, cognitive performance, evaluated by novel object recognition test and passive avoidance task, was impaired only in male offspring. HFD altered plasma tryptophan metabolism by increasing kynurenine pathway activity and reducing serotonin in both sexes. Sex-specific neurochemical changes emerged, with males showing increased levels of the neurotoxic metabolite 3-hydroxykynurenine, whereas females exhibited lower serotonin levels in the prefrontal cortex (PFC) and hippocampus (HIPP). Following HFD exposure, Aβ oligomers were centrally increased. In male, HFD induced increase levels of the neuroinflammatory marker NF-ΚB, while the content of the brain derived neurotrophic factor (BDNF) was reduced. Conversely, HFD females showed increased BDNF levels. These findings indicate that prolonged HFD exposure may differentially program brain vulnerability in males and females, contributing to the pathogenesis of obesity-related neuropsychiatric disorders and highlighting the need for sex-specific therapeutic strategies. • Long-term HFD causes depressive-like behaviors especially in male young mice. • Long-term HFD causes cognitive decline only in male young mice. • HFD alters central and peripheral TRP catabolism in a sex-dependent manner. • HFD alters central amyloid oligomers, BDNF and NF-kB levels in a sex-dependent way.