Fructose-mediated NLRP3 activation induces inflammation and lipogenesis in adipose tissue

Adipose tissue plays a crucial role in energy intake and regulation of metabolic homeostasis. Fructose consumption implicates in development and progression of metabolic dysfunctions. Fructose is a lipogenic sugar known to induce inflammatory response. However, the role of specific inflammatory signal such as nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) in fructose-induced inflammatory response and its relevance to lipogenesis in adipose tissue are elusive. We assessed NLRP3 activation and its significance in inflammatory response and lipogenesis in epididymal adipose tissue of 60% fructose diet (HFrD)-fed rats. The long-term consumption of HFrD led to impairment of glucose metabolism, development of visceral adiposity, insulin resistance, and elevation of serum triglycerides level, accompanied by activation of NLRP3 in adipose tissue. NLRP3 inflammasome activation in adipose tissue was associated with up-regulated expression of Nlrp3, Asc, and Caspase-1, and raised caspase-1 activity, which resulted in increased expression of IL-1β and IL-18 and secretion of IL-1β. Moreover, lipid accumulation and expression of transcription factors exacerbating accumulation of lipids were augmented in adipose tissue of HFrD-fed rats. Treatment with glyburide, quercetin or allopurinol corrected HFrD-induced dyslipidemia or hyperuricemia, and blocked NLRP3 activation, leading to mitigated inflammatory signaling and lipid accumulation in adipose tissue, improved glucose tolerance and insulin sensitivity in HFrD-fed rats. These data suggest the role of NLRP3 inflammasome to establish linkage among inflammation, lipid accumulation and insulin resistance in adipose tissue, and targeting NLRP3 inflammasome may be a plausible approach for prevention and management for fructose-induced metabolic impairments.