Apolipoprotein D modulates obesity-linked inflammation and metabolic syndrome development in a sex dependent manner

Obesity, or the excessive and often deleterious accumulation of body fat, is a disease that has gained in prevalence over time. This fat accumulation is often the starting point of other obesity-related pathology, such as low-grade systemic inflammation, insulin resistance, glucose intolerance, hepatic steatosis, behavioral changes including increased anxiety and depression, renal dysfunction, and cardiovascular problems, all of which are costly on a personal and societal level. Apolipoprotein D (ApoD), a circulating lipocalin that accumulates in largely in the liver, has been implicated in a number of processes such as altered lipid metabolism in the liver, inflammation modulation and decreased oxidative stress through direct neutralization of lipid peroxides. Knowing that ApoD has metabolism modulating, anti-inflammatory, and antioxidant proprieties, we set out to find if overexpression of ApoD could mitigate obesity linked pathologies. For this, male and female transgenic mice overexpressing the human ApoD were put on a high fat, high sugar diet for 12 weeks. Metabolic, inflammatory, oxidative stress and behavior parameters were assessed. Male mice overexpressing HApoD were significantly more protected from inflammation, liver steatosis and metabolic deterioration caused by the diet, while overexpression of ApoD in females was detrimental for liver inflammation and steatosis, and was detrimental for glucose homeostasis. Circulating hormone levels analysis revealed an altered profile in transgenic mice, and progesterone receptor activation was higher in transgenic mice fed the high fat, high sugar diet. This study demonstrates for the first time sex differences related to ApoD's function, which is most likely related to progesterone metabolism.