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Interleukin Deficiency Leads To Hyperphagia, Obesity, and Insulin Resistance

« Back to Volume 22, Issue 4, December 2006 - Table of Contents

Serum concentrations of interleukin 18 ([IL-18] OMIM 600953, chromosome 11q22.2-q22.3), an interferon- g inducing factor that augments natural killer cell activity and perhaps contributes to chronic inflammatory disorders such as Crohn’s disease, are increased in patients with obesity, type 2 diabetes mellitus, and polycystic ovarian syndrome. Interleukin-18 is synthesized and secreted by hepatic Kuppfer cells and macrophages. The biologic effects of IL-18 are mediated by its binding to a specific cytokine receptor (IL-18R1; OMIM 604494, chromosome 2q12) and receptor accessory protein (IL-18RAP; OMIM 604509, chromosome 2q12). The biologic activity of IL-18 is inhibited by binding to an IL-18-binding protein ([IL-18BP] OMIM 604113, chromosome 11q13) which prevents the interaction of IL-18 with IL-18R1.

Netea et al demonstrated in the mouse that loss (“knock out”) of IL-18 (IL-18 ^-/-), or its receptor (IL-18r ^-/-), or excessive (“knock in”) production of IL-18bp (thus neutralizing endogenous IL-18) results in hyperphagia and obesity associated with hyperinsulinemia and insulin resistance primarily confined to muscle and adipose tissues, hyperglucagonemia, hyperglycemia and impaired glucose tolerance, increased hepatic glucose output, hyperlipidemia, and vascular atherosclerosis. Thus,
IL-1 8 ^-/- mice had characteristics of metabolic syndrome. In IL-1 8 ^-/- mice, relative to wild-type (wt) mice, body weight was normal at 3 months of age but substantially elevated by 6 months, and became progressively greater thereafter. The increased weight of the IL-18 ^-/- mouse was due to excessive caloric intake and augmented fat accumulation, while basal metabolic rate remained normal. Peripheral administration of leptin and central injection of recombinant IL-18 decreased appetite; peripheral administration of IL-18 restored glucose homeostasis in the IL-1 8 ^-/- mouse. The increase in hepatic glucose production in the IL-1 8 ^-/- mouse was due to decreased phosphorylation of the transcription factor—signal transducing and activation of transcription (STAT)3—that resulted in accentuated gluconeogenesis due in part to increased expression of phosphoenolpyruvate carboxykinase (PEPCK-1). The investigators concluded that IL-18 is another component of the complex of factors that regulate appetite and energy metabolism.

Netea MG, Joosten LA, Lewis E, et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature Med. 2006;12:650–656.

Converting metabolic signals into anorectic (appetite-suppressing) responses in the hypothalamus. Major classes of anorectic signals in the hypothalamus include nutrients such as free fatty acids (FFA), glucose, leucine and other branched-chain amino acids (BCAA), and hormones such as insulin and leptin. Cota et al1 show that BCAA potently activates signaling through the mTOR complex (TORC)-1. FFA and glucose may also regulate TORC1 in the arcuate nucleus, either directly or indirectly (via cellular AMP/ATP levels and AMPK activity). The regulation of cellular malonyl–coenzyme A levels may mediate a component of feeding control by AMPK in parallel with AMPK effects on mTOR. In addition to potentially regulating TORC1 indirectly through the inhibition of AMPK, insulin and leptin may also control mTOR via the PI3K or other pathways. Regulation of FOXO-dependent transcription and ATPdependent potassium (KATP) channels probably also contributes to PI3K-dependent anorexia. Activation of STAT3-dependent transcription by leptin is a crucial short- and long-term regulator of feeding. Although the mediators of TORC1-dependent anorexia are not clear, S6K1 and downstream events such as protein synthesis are likely to be involved.

Editor’s Comment

To the enlarging list of anorexigenic factors (insulin, leptin, α-MSH, cocaine and amphetamine regulated transcript [CART], branched chain amino acids, and other nutrients) that regulate appetite and energy expenditure, IL-18 may now be added. One could speculate that an analogue of this cytokine might be an effective therapeutic agent for the management of patients with obesity and/or metabolic syndrome. Recent studies have further defined cellular mechanisms involved in appetite regulation. The serine-threonine kinase mTOR (mammalian target of rapamycin) has been identified as a critical regulatory factor in the integration of peripheral hormonal and nutritional (glucose, fatty acids, amino acids) signals (Figure) that decrease appetite.^1,2 Leptin, insulin, and various nutrients suppress appetite in part by activating mTOR. This protein is a component of the multi-protein complex TORC1 that senses energy availability; when energy is sufficient, TORC1 permits cell growth and enables leptin production by the white fat cell. The TORC1 is particularly active in the arcuate nucleus, the site in which the central regulation of energy balance is present. Leptin also decreases appetite and energy utilization by inhibiting synthesis of orexigenic agouti-related peptide (Agrp) in the arcuate nucleus, an activity mediated through phosphatidylinositol 3 kinase (PI3K) but antagonized by the forkhead box-containing protein of the O subfamily (FOXO1), a DNA binding protein.³

Allen W. Root, MD

References - (linked to )

« Back to Volume 22, Issue 4, December 2006 - Table of Contents

Last Updated: 6/12/2009