Effects of Cytokines on Food Intake and Obesity

A relationship exists between cytokines and both leptin (L4146) and insulin ( I1507). Proinflammatory cytokines increase leptin levels while leptin regulates pro- and anti-inflammatory cytokine production. Interleukin-1 (IL-1) is a proinflammatory cytokine that promotes the release of corticotrophin releasing factor (CRF) (C3042), which suppresses feeding behavior. Excess IL-1 signaling induced by leptin suppresses feeding behavior via melanocortin receptors (H2396) [1]. In addition, IL-1 appears to modulate lipid metabolism by suppressing lipoprotein lipase (LPL) (L2254), the enzyme regulating the disposal of lipid stores in the body [1]. Interleukin-6 (IL-6) (I3268) is another proinflammatory cytokine secreted from adipocytes whose circulating levels are elevated in obese individuals. IL-6 is associated with the insulin resistance of obesity and type 2 diabetes [2]. Tumor necrosis factor-α (TNF-α) (T6674) is another proinflammatory cytokine secreted from adipocytes whose overproduction may be the factor that negatively influences the ability of insulin to stimulate glucose transport in adipocytes [3]. Ciliary neurotrophic factor (CNTF) (C3710), a tropic factor first identified in the ciliary ganglion, appears to act similarly to leptin. In leptin-deficient ob/ob mice, CNTF administration has been shown to reduce adiposity, hyperphagia and hyperinsulinemia, similar to leptin [4]. Systemic administration of CNTF activates the JAK/STAT pathway in the ARC, overlapping with those pathways activated by leptin [5]. Unfortunately, Axokine, a modified version of CNTF, showed disappointing results in Phase III trials for the treatment of obesity.

References:

1. Matsuki, T., et al., IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions. J. Exp. Med., 198, 877-888 (2003).


2. Klover, P.J., et al., Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes, 52, 2784-2789 (2003).


3. Lafontan, M. and Berlan, M., Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol. Sci., 24, 276-283 (2003).


4. Zvonic, S., et al., The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J. Biol. Chem., 278, 2228-2235 (2003).


5. Flier, J.S., Obesity Wars: Molecular progress confronts an expanding epidemic. Cell, 116, 337-350 (2004).

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