Iso-α-acids, bitter components of beer, prevent obesity-induced cognitive decline

Abstract

Dementia and cognitive decline have become worldwide public health problems, and it was recently reported that life-style related diseases and obesity are key risk factors in dementia. Iso-α-acids, hop-derived bitter components of beer, have been reported to have various physiological functions via activation of peroxisome proliferator-activated receptor γ. In this report, we demonstrated that daily intake of iso-α-acids suppresses inflammations in the hippocampus and improves cognitive decline induced by high fat diet (HFD). Body weight, epididymal fat weight, and plasma triglyceride levels were increased in HFD-fed mice, and significantly decreased in iso-α-acids supplemented HFD-fed mice. HFD feeding enhances the production of inflammatory cytokines and chemokines, such as TNF-α, which was significantly suppressed by iso-α-acids administration. HFD-induced neuroinflammation caused lipid peroxidation, neuronal loss, and atrophy in hippocampus, and those were not observed in iso-α-acids-treated mice. Furthermore, iso-α-acids intake significantly improved cognitive decline induced by HFD-feeding. Iso-α-acids are food derived components that suppressing both lipid accumulation and brain inflammation, thus iso-α-acids might be beneficial for the risk of dementia increased by obesity and lifestyle-related diseases.

Figure 1

Dietary intake of iso-α-acids prevent excess body weight and adipose tissue gain induced by high fat diet intake. Male C57BL/6 J mice were fed either a normal diet, high fat diet (HFD), or HFD with 0.05% (w/w) iso-α-acids (IAA) supplementation for 8 weeks. (a) Body weight was measured every week. (b) Epididymal fat weight at the eighth week of feeding, when mice were sacrificed. All values are expressed as means ± SEM (n = 10 mice per group). (a) **P < 0.01 versus ND fed group, ^††P < 0.01 versus HFD fed group. (b)**P < 0.01, *P < 0.05 versus each group.

Figure 2

Iso-α-acids suppress obesity-induced neuroinflammation and lipid peroxidation in the hippocampus. Left hippocampus of ND-, HFD-, and HFD supplemented with iso-α-acids- fed mice were homogenated in TBS buffer and centrifuged supernatants were collected at the eighth week. (a–c) The levels of IL-1β (a), IL-6 (b) and TNF-α (c) were measured using a multi-plex assay. (d) The ratio of variation of the TNF-α level to that of body weight gain was calculated by the following formula: (individual TNF-α concentration minus average TNF-α concentration in ND-fed mice)/(individual body weight minus average body weight in ND-fed mice). (e) The level of malondialdehyde (MDA) in the hippocampus was measured by ELISA. All values are expressed as means ± SEM (n = 10 mice per group). **P < 0.01, *P < 0.05 versus each group.

Figure 3

High fat diet loading induces atrophy and neurodegradation, which was suppressed by iso-α-acids supplementation. (a) Weights of hippocampus from ND-, HFD-, and HFD supplemented with iso-α-acids- fed mice, at the eighth week of feeding. (b–d) The levels of phosphorylated CREB (b), total CREB (c), and BDNF (d) in the hippocampus, which are regarded as indicators of neuronal cells. All values are expressed as means ± SEM (n = 10 mice per group). **P < 0.01, *P < 0.05 versus each group.

Figure 4

The anti-obesity effect of iso-α-acids leads to prevention of obesity-induced cognitive decline. The object recognition test (ORT; a,b) and object location test (OLT; c,d) were conducted at the seventh week. (a) Time spent in exploring novel or familiar objects over 5 min in the ORT. (b) Discrimination index (DI; (time spent investigating novel object minus time spent investigating familiar object)/(total exploration time)). (c) Time spent exploring novel or familiar locations over 8 min in the OLT. (d) Discrimination index. All values are expressed as means ± SEM (n = 8–10 mice per group). (e) The ratio of the DI score variation to the body weight gain was calculated by the following formula: (individual DI score minus average DI score in ND-fed mice)/(individual body weight minus average body weight in ND-fed mice). **P < 0.01, *P < 0.05 versus each group.