Lipopolysaccharide aggravates depressive‐like behavior via increasing microglial inflammation, decreasing microglial ramification, and altering tryptophan level in obese rats

Abstract

AbstractBackgroundLong‐term high‐fat diet consumption has been shown to induce endotoxemia, microglial dysmorphology, and depressive‐like behavior (1, 2). Previous studies demonstrated that the kynurenine pathway of tryptophan metabolism plays an important role on mediating the depressive‐like behavior in response to inflammation (3, 4). However, the effects of lipopolysaccharide as endotoxin on the alterations of microglial profiles/morphologies, changes in brain metabolites, as well as depressive‐like behavior in obese condition have never been investigated.MethodSixteen male Wistar rats were randomly divided into two groups to fed with either normal diet (ND, n = 8) or the high‐fat diet (HFD, n = 8) for 12 weeks. At week 12, animals in each dietary group were subsequently divided into two subgroups (n = 4 per subgroup) to receive either a single dose of vehicle (1 ml of 0.9% normal saline solution, intraperitoneal (i.p) injection, or lipopolysaccharide (LPS, 0.5 mg/kg, i.p. injection). After the injections for 12‐16 hours, all animals were measured depressive‐like behaviors and blood was collected. Then, animals were sacrificed, and brains were obtained for further molecular investigation.ResultWe found that LPS‐treated HFD‐fed rats, not LPS‐treated ND‐fed rats and vehicle‐treated HFD‐fed rats, increased microglial IL‐1β mRNA level (p<0.05, Figure 1). In addition, LPS‐treated ND‐fed rats and vehicle‐treated HFD‐fed rats significantly decreased microglial ramification as indicated by decreasing branch points, whereas LPS‐treated HFD‐fed rats showed the lowest microglial branch points (p<0.05, Figure 1). The level of brain tryptophan and depressive‐like behavior increased in both LPS‐treated ND‐fed rats and vehicle‐treated HFD‐fed rats, when compared with those of vehicle‐treated ND‐fed rats (p<0.05, Figure 1). Interestingly, LPS‐treated HFD‐fed rats showed the highest brain tryptophan level and freezing duration during Force Swimming Test (FST) (p<0.05, Figure 1).ConclusionThese findings indicate that LPS aggravates depressive‐like behavior in obese condition by increased microglial hyperactivation, and possibly be related to its regulation of kynurenine metabolism.