Inflammation and Obesity: A vicious cycle

Metabolic and immune processes are tightly interconnected and share numerous cytokines. Two crucial signaling molecules that link inflammation and metabolism are IL-1 and IL-18. These interleukins undergo proteolytic maturation by caspase-1, which must first be activated by the enzymatic action of a cytosolic protein complex know as the NLRP3 inflammasome. Studies have suggested a close relationship between IL-1β, the NLRP3 inflammasome and the metabolism of lipids and carbohydrates. The NLRP3 inflammasome has been proposed as a key player in adipocyte differentiation and high fat diet (HFD)-induced obesity.

Inflammasome activation occurs through two signals. First a priming signal promotes transcription. The second stimulus promotes the assembly of NLRP3, ASC and pro-caspase-1 units. Several secondary metabolic stress signals that the inflammasome may recognize have been proposed including glucose, palmitate, ceramides, cholesterol crystals, islet amyloid polypeptide (IAPP), and ROS (Reactive Oxygen Species).

Diet-induced obese NLRP3knockout mice have fewer pro-inflammatory cytokines in adipose tissue compared to similarly obese wild-type mice. An analysis of adipocytes from lean and obese women indicates a significant upregulation of NLRP3, ASC and IL-1β in obese subjects. Mice that are deficient in NLRP3 or caspase-1 demonstrate increased adipogenesis when compared to wild type controls.

As adipocytes differentiate, the space between them decreases and the amount of cell-to-cell contact increases. Adipocytes are highly sensitive to their mechanical environments and can actually release cytokines and modulate differentiation in response to mechanical stress and strain, a process that seems to involve the NLRP3 inflammasome.

A relationship between the NLRP3 inflammasome and metabolic syndrome has been gradually uncovered over the past couple of decades. One of the most common consequences of metabolic syndrome is the development of type 2 diabetes mellitus. Deleting any of the three components of the NLRP3 inflammasome from mice improves glucose tolerance and insulin sensitivity. Other consequences of metabolic syndrome such as atherosclerosis and gout have also been associated with the action of the NLRP3 inflammasome. Thus, the manipulation of the NLRP3 complex, as well as signal pathways downstream and upstream of its activation, present a promising avenue for the adjustment of homeostasis and the management of metabolic syndrome.


Originally published at www.bioernst.com on March 12, 2016.