ABSTRACT
Obesity is associated with a chronic inflammation of the adipose tissue that exacerbates and may underlie insulin resistance and metabolic disease. This concept originated from the finding that the tumor necrosis factor-alpha (TNF-α) proinflammatory cytokine was elevated in the adipose tissues of obese mice and in the circulation of morbidly obese humans (Hotamisligil et al., 1993, Hotamisligil et al., 1995). Transgenic mice lacking TNF-α (Uysal et al., 1997) or elements of its
8.1 Adipose Inflammation in Obesity ................................................................. 127 8.2 Glucocorticoids and Inflammation ............................................................... 128
8.2.1 Glucocorticoids and Adipose Inflammation ..................................... 129 8.3 11β-Hydroxysteroid Dehydrogenase Type 1 ................................................. 130
8.3.1 Substrate Levels for 11β-HSD1 ......................................................... 130 8.3.2 11β-HSD1 in Adipocytes .................................................................. 132 8.3.3 Regulation of Adipocyte 11β-HSD1: Implications for Adipose
Glucocorticoid Action ....................................................................... 132 8.4 11β-HSD1 in Obesity .................................................................................... 133
8.4.1 Visceral Fat 11β-HSD1: A Pronounced Contribution to Portal Insulin Resistance? ........................................................................... 134
8.5 Transgenic Manipulation of Adipose 11β-HSD1 .......................................... 135 8.5.1 Adipose 11β-HSD1 Overexpressing Mice ........................................ 135 8.5.2 Global 11β-HSD1 Knockout (11β-HSD1-/–-) Mice ........................... 136 8.5.3 Adipose 11β-HSD2 Overexpressing Mice: Model of Adipose-
Specific Glucocorticoid Deficiency .................................................. 137 8.6 Downregulation of 11β-HSD1 as Adaptation to Chronic Fat Feeding ......... 138 8.7 11β-HSD1 and Macrophages ........................................................................ 138 8.8 Other Sites of 11β-HSD1 Expression Pertinent to Adipose Inflammation ... 140 8.9 11β-HSD1 Inhibitors as Therapeutics ........................................................... 140 8.10 Conclusions ................................................................................................... 141 References .............................................................................................................. 141
downstream inflammatory signalling cascade confirmed that obesity and its associated insulin-resistance and diabetes were ameliorated when inflammatory pathways were impaired (Yuan et al., 2001, Hirosumi et al., 2002, Kaneto et al., 2004, Tuncman et al., 2006).
