The consumption of Western diets — high in sugar and saturated fat, combined with sedentary behavior — has led to an epidemic of lifestyle-associated, non-communicable diseases, including type 2 diabetes, obesity, and cardiovascular conditions1. A growing body of evidence has linked these health issues to a 'silent' inflammation, whose conceptualization and underpinning mechanisms are described in the metaflammation theory2,3.
Rethinking inflammation
Metaflammation is a term first introduced in 2006 to describe a type of chronic, low-grade inflammation observed in metabolically impactful tissues, such as adipose tissue, pancreatic islets, the liver, and even the brain, causing severe systemic damage over time, which leads to disrupted metabolic pathways and pathogenesis2. The discovery of metabolically triggered inflammation has led to a paradigm shift from the traditional view of inflammation as an acute, short-term response to infection or external injury2.
Adipose tissue: the usual suspect
For a long time, excess adipose tissue was seen as the primary driver of metaflammation4. As fat mass expands, the fat-storing cells, known as adipocytes, suffer hypoxia and mechanical stress. The overloaded adipose tissue loses its ability to store excess fat efficiently, causing the formation of danger-associated molecular patterns (DAMPs). Reactive oxidative species (ROS) and lipid byproducts, like ceramides and cholesterol from free fatty acids, are released into the bloodstream, further contributing to systemic inflammation4,5. Moreover, the stressed adipocytes secrete pro-inflammatory molecules, such as adipokines and cytokines (e.g. leptin, TNF-α, IL-1β) to recruit macrophages into the adipose tissue, where they shift to a pro-inflammatory state4,5. Over time, this localized 'sterile' inflammation spills over into systemic circulation, contributing to metabolic dysregulation (e.g. insulin resistance) and disease onset4,5. In short, obesity was thought to be the predominant, and linear cause of metaflammation. However, as research has advanced, it has become clear that while adipose tissue plays an essential role in metaflammation, it is only one part of a much more complex network4.
The gut-brain axis in metaflammation
Recent studies have shown that metaflammation in the brain, particularly in the hypothalamus, can occur early in the process of obesity development, often before significant fat accumulation6. This observation raised the question of whether hypothalamic inflammation could actually be the cause of obesity rather than a consequence6. The hypothalamus is the most important regulatory center in the brain, controlling hunger, satiety, and energy expenditure via hormones, such as leptin and insulin6. It has been shown that even a short exposure to high-fat, high-sugar diets can trigger reactive gliosis, a process involving the chronic activation of microglia and astrocytes in the brain. This leads to the release of pro-inflammatory cytokines, promoting metaflammation and weakening of the blood-brain-barrier6. Consequently, dietary fats easily accumulate in the hypothalamus, impairing insulin and leptin signaling pathways, which in turn causes dysregulated appetite control and weight gain due to increased food consumption6.
The constant excess of calorie-dense food is shown to adversely alter the composition of the gut microbiota, increasing intestinal permeability and thereby allowing bacterial endotoxins, also known as lipopolysaccharides (LPS), to enter the bloodstream1,7 - further fueling this inflammatory cycle.
The real culprits: TLR4 & NLRP3
LPS is a well-known pathogen-associated molecular pattern and is recognized by Toll-like receptor 4 (TLR4), one of the pattern recognition receptors (PRRs) associated with metaflammation8. Activation of TLR4 by LPS, free fatty acids, and ceramides was found to disrupt leptin6,9 and insulin6 signaling through inflammatory pathways, including IKKb, NF-κB, and JNK, as well as NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome priming5. Enhanced IKKb/NF-κB signaling in the hypothalamus interferes with the leptin pathway by affecting STAT3 phosphorylation and upregulating SOCS3, a negative regulator of leptin signaling9. The activation of NLRP3, a key amplifier of inflammatory responses, allows for a rapid response to the aforementioned DAMPs, ROS and cholesterol crystals. Additionally, other 'sterile' DAMPs, such as beta-amyloids, ATP, and monosodium urate crystals, can trigger the NLRP3 inflammasome, resulting in IL-1β secretion as well as pyroptotic cell death5,11.
Excessive IL-1β production has been demonstrated to play a key role in obesity-induced diabetes by altering the insulin pathway. It reduces the translocation of the glucose transporter type 4 and inhibits insulin receptor functions, ultimately decreasing glucose uptake and disrupting insulin sensitivity in peripheral tissues, which promotes insulin resistance10. Notably, blocking NLRP3 activation has been found to improve insulin sensitivity13.
Taming NLRP3 is key
Thus, NLRP3 holds great potential as a drug target for a range of diseases, including obesity, neurodegenerative, and cardiovascular conditions5. Indeed, NLRP3 knockout and prophylactic dosing with the NLRP3 inhibitor MCC950 (CP-456773) protected animals against diet-induced obesity12. Although the precise mechanisms linking NLRP3 inhibition and reduced metaflammation to weight loss are not fully understood, it has been suggested that these effects mainly result from lowering the chronic inflammation in the hypothalamus12. Reduced central nervous system (CNS) inflammation has been shown to restore insulin and leptin sensitivity6. This improvement leads to normalized eating behaviors, a decrease in calorie intake, and subsequently, a healthy microbiota composition and weight loss.
A promising new drug NT-0796
Interestingly, preestablished obesity was reversed using NT-0796, a novel clinical-stage NLRP3 inhibitor12. NT-0796 is orally available, exhibits good systemic distribution, and can cross the blood–brain barrier, opening the possibility to treat a number of conditions associated with chronic inflammation of the periphery or CNS12.
Initially developed by NodThera as a lead clinical-stage therapy for Parkinson's disease, NT-0796 has also demonstrated nearly equivalent effectiveness, in promoting weight loss, to Novo Nordisk’s blockbuster GLP-1 receptor agonist semaglutide, marketed as Wegovy®12. Moreover, NT-0796 treatment reduces the expression of disease-relevant metabolic and cardiovascular inflammatory biomarkers like fibrinogen, VCAM-1 (vascular cell adhesion protein 1), and PCSK9 (proprotein convertase subtilisin/kexin type 9)12. It also decreases levels of GFAP (glial fibrillary acidic protein), a key marker of reactive gliosis in the brain12.
Uncovering that NLRP3 and other PRRs do not only detect pathogens but are also crucial in driving metaflammation due to nutrient sensing has unveiled exciting new targets. Beyond innovative drugs that curb pro-inflammatory PRR activation, lifestyle changes like caloric restriction and balanced diets represent promising candidates to counteract metaflammation and its detrimental effects on our health11,12. Overall, we are what we eat.
References
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2. Hotamisligil GS, 2006. Nature. 14;444(7121):860-7.
3. Franceschi C, et al., 2017. Trends Endocrinol Metab.;28(3):199-212.
4. Lumeng CN, Saltiel AR. 2011. J Clin Invest. 121(6):2111-7.
5. Ramachandran R, et al., 2024. Exp Mol Med. ;56(7):1488-1500.
6. Sonnefeld L, et al., 2023. Eur J Endocrinol. 188(3):R37-R45.
7. Cani PD, et al., 2007. Diabetes. 56(7):1761-72.
8. Saltiel AR, Olefsky JM, 2017. J Clin Invest. 127(1):1-4.
9. de Git KC, Adan RA,. 2015. Obes Rev. 16(3):207-24.
10. Jager J, et al., 2007. Endocrinology. 148(1):241-51.
11. Harrison D, et al., 2023. J Med Chem. 66(21):14897-14911
12. Thornton et al., 2024. J Pharmacol Exp Ther. 388(3):813-826.
13. Vandanmagsar B, et al., 2011. Nat Med. (2):179-88.
