Cell death and inflammation during obesity: “Know my methods, WAT(son)”

Fig. 1. Crosstalk between NF-κB and metabolic pathways. TNF induces NF-κB activation via the assembly of a complex which includes RIPK1, the E3 ligases cIAP1/2 and LUBAC which ubiquitinate and stabilise the complex, and the kinase complexes IKKɑ/β/ɣ (NEMO) and TAK1/TAB1/2. The thereby activated IKKɑ/β/ɣ(NEMO) complex promotes degradation of the inhibitor of kB (IκB) and activation of NF-κB (here exemplified as p50/RelA/p65) which translocates to the nucleus and activates target genes. Activation of NF-κB then results in the inhibition of AMPK and Insulin signalling (red arrows and blockers). AMPK is a sensor of low ATP and induces a plethora of catabolic processes to uptake/produce energy whilst blocking processes that required energy (ATP) (green arrows and blockers). Activation of both Adiponectin Receptor (AdR) and Leptin Receptor (LepR) induces AMPK phosporylation and glucose uptake. Insulin sensing by Insulin Receptor (IR) is crucial for glucose uptake by activating Akt and allowing the activity of glucose transporters (GLUT4).

Fig. 2. Different ways to die upon activation of death receptors of the TNFR1 family. Under pathological conditions, TNF can induce the formation of cell death complexes. Apoptosis is induced by formation of a RIPK1/FADD/Caspase-8 (Casp-8) complex. This results in cleavage and activation Casp-3 and apoptosis or, in certain conditions, Gasdermin D (GsmdD) and pyroptosis. Necroptosis is induced by recruitment of RIPK1 and RIPK3 which are activated by autophosphorylation. This leads to phosphorylation of MLKL which subsequently forms pores in the membrane. Canonical pyroptosis requires a priming event to upregulate the expression of inflammasome components, NRLP3, ASC and Caspase-1, such as TLR4 activation by Lipopolysaccharides (LPS). Pyroptosis is induced upon activation of NLPR3 by DAMPs such as ATP. Inflammasome formation consists of oligomerised NRLP3/ASC/pro-Caspase-1 (Casp-1). This platform leads to activation of Casp-1 which cleaves GsdmD that forms pores in the membrane and induces pyroptosis. Casp-1 also processes pro-IL-1β maturation which is then released by GsdmD pores. Pyroptosis can also be induced by a GsdmE, which can be cleaved and activated by Casp-3. GsdmE can amplify…