Table 3.

In vivo Studies Implicating NF-κB in Adipocyte Immunometabolism.

Authors	Title	Year published	Major findings	Comments
Zamboni et al. [113]	“Adiponectin gene expression and adipocyte NF-κB transcriptional activity in elderly overweight and obese women: inter-relationships with fat distribution, hs-CRP, leptin, and insulin resistance”	2007	• iκBα gene expression is negatively correlated with abdominal adiposity in humans • This indirectly implies that abdominal adiposity is associated with greater activity of NF-κB itself	• A limitation of this study was that whole adipose tissue was used, unknowable which cell types are responsible for various correlations
Chiang et al. [114]	“The protein kinase IKKepsilon regulates energy balance in obese mice.”	2009	• HFD consumption results in a 5-fold increase in NF-κB activity in visceral and subcutaneous WATs • Expression of IKKε increased dramatically in adipocytes from mice on HFD (far more so than in cells of the SVF) • Smaller, more numerous adipocytes in Ikbke-/- mice; animals exhibited increased energy expenditure and less HFD-induced weight gain (despite eating more calories) • Dramatically increased Ucp1 expression in WAT of Ikbke-/- mice • Improved glucose, lipid homeostasis, and insulin signaling in the HFD-fed KO animals • Transfection of an IKKε vector into 3T3-L1 adipocytes reduces glucose uptake • Protection of Ikbke-/- mice from hepatic steatosis • Significantly reduced chronic inflammation seen in multiple tissues of HFD-fed Ikbke-/- mice	• Manuscripts identified a major new player in adipose tissue inflammation • IKKε, an established target of classical NF-κB signaling, promotes insulin resistance and impairs adipogenesis in adipose tissues • Loss-of-function results suggest that IKKε mediates major actions of NF-κB in WAT • Effects appear to be largely due to IKKε deficiency in adipocytes, but an adipocyte-specific model could still be warranted
Tang, T et al. [97]	“Uncoupling of inflammation and insulin resistance by NF-κB in transgenic mice through elevated energy expenditure.”	2010	• Significant increase in expression of NF-κB target genes in WAT of aP2-p65 transgenic mice on a normal diet (expected result) • aP2-Rel-A/p65 transgenic animals display elevated energy expenditure and decreased epididymal fat mass. • p65/Rel-A inhibits adipogenesis • Resistance of aP2-p65 mice to diet-induced obesity • Enhanced insulin sensitivity of aP2-p65 mice on HFD • Similar phenotype in global Nfkb1-/-(p50) KO mice	• Rela overexpression model in adipocytes and macrophages • Energy expenditure could be an artifactual result (since aP2-p65 KO mice also displayed increased energy expenditure [115]) • Enhanced insulin sensitivity is surprising but possibly a result of increased energy expenditure and lower fat pad mass
Jiao, P et al. [116]	“Constitutive activation of IKKβ in adipose tissue prevents diet-induced obesity in mice”	2012	• Body weights of aP2-IKKβ transgenic animals are reduced on both normal and high-fat diets • Reduced fat pad weights in the Tg mice • Expression of IL-6 and MCP-1 increased in aP2-IKKβ WAT on both chow and HFD as well as in aP2-IKKβ isolated adipocytes • Macrophage infiltration may have been enhanced in aP2-IKKβ Tg mice (not quantified in this study) • Increased food intake and energy expenditure in aP2-IKKβ Tg mice • Increased expression of fatty acid oxidation and thermogenesis-related genes in BAT and muscle • Circulating levels of IL-6 and TNF-α increased in aP2-IKKβ Tg mice • Improved insulin sensitivity • Animals largely phenocopy aP2-p65 Tg mice	• Results corroborate Tang et al. [97] with very similar phenotypes • Increased energy expenditure appears to be linked to elevated IL-6 in both models • Suggests that overall energy balance can override local inflammation in WAT • Also suggests that local inflammation in WAT cannot drive systemic insulin resistance unless there is a chronic positive energy balance
Gao, Z et al. [117]	“p65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice”	2015	• Adipocyte/macrophage p65-κO reduces adipose inflammation in lean mice • Surprisingly, the same knockout scheme worsened inflammation in obese mice • Adipocyte apoptosis was increased in the KO mice, possibly leading to a secondary inflammation • KO obese mice displayed increased energy expenditure, possibly explaining lack of signs of insulin resistance despite increased WAT inflammation	• What transcription factors are involved in stimulating apoptosis-induced inflammation in the absence of p65? • Would similar effects be observed using a true adipocyte-specific knockout scheme (Adipoq-Cre?)