An ever-growing epidemic, obesity is a chronic medical condition where excess body fat has accumulated to the point it may cause a multitude of health disorders. Several studies have also reported increased rates of age-related cognitive decline in obese humans, including atrophy of the medial temporal lobes and the hippocampus, which all play crucial roles in memory and learning. However, there is also contrasting research refuting these claims, confusing the issue. Now, a study from researchers at the Medical College of Georgia shows excess fat around the waist and abdomen signals the brain’s immune cells, known as microglia, to attack healthy tissue in the brain, causing inflammation and damaging cognition. The team states their results add to the growing body of work that links being severely overweight or obese in middle or old age to dementia. The opensource study is published in The Journal of Clinical Investigation.
Previous studies have shown that midlife obesity increases the risk of dementia in late life; however, the link between being overweight in midlife and cognitive impairment is unclear. To date, it has been shown excessive visceral fat, body fat that’s stored within the abdominal cavity, causes an inflammatory immune response within the whole system. This inflammatory response was found to involve the NLRP3 inflammasome, a protein complex that initiates cell death and triggers the release of the cytokine interleukin-1 beta (IL-1β). Cytokines are molecules secreted by peripheral immune cells, as well as microglia, astrocytes, and neurons in the central nervous system, and are known to impact neural circuitry. The current study investigates whether inflammation caused by visceral fat involving NLRP3 initiates microglial activation and cognitive impairment by increasing levels of IL-1β.
The current study ablates NLRP3 from mice to show the mice are protected against obesity-induced inflammation in the brain and cognitive impairment. Results show when visceral fat was transplanted from obese mice and the NLRP3-knockout obese mice into lean mice, the transplant from the mice missing NLRP3 had no effect. Data findings show the visceral fat transplant from the obese mice who were able to produce NLRP3 increased levels of IL-1β in the hippocampus and impaired cognition in lean mice.
Results show transplanting visceral fat causes the same impact as obesity induced by a high-fat diet, whilst increasing brain levels of IL-1β and activating microglia; mice missing IL-1β’s receptor on their microglia exhibited neuroprotective behavior. The lab states there are many therapeutics currently available that target IL-1β for conditions such as rheumatoid arthritis and Crohn’s disease which could provide neuroprotection for the severely overweight and obese. They also note obesity-induced inflammation, which occurs over a period of years, appears to follow the same trajectory as inflammation in a number of chronic inflammatory-based disorders.
The team surmises they have identified the specific signal generated in visceral fat, that can transverse the blood-brain barrier to activate microglia and impair cognition. For the future, the researchers state understanding and manipulating microglial interactions with synapses and circuits that have been activated by cytokines may reveal a number of novel therapies for the prevention and treatment of neurodegeneration.
Source: Medical College of Georgia
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