Enhanced Expressions of mRNA for Neuropeptide Y and Interleukin 1 Beta in Hypothalamic Arcuate Nuclei during Adjuvant Arthritis-Induced Anorexia in Lewis Rats

Abstract

Objective: Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1β is involved in the central induction of anorexia, we studied its expression in the nARC as well. Methods: AA was induced to Lewis rats using complete Freund’s adjuvant. On days 12, 15 and 18 after complete Freund’s adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1β were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1β were determined by TaqMan RT-PCR from isolated nARC. Results: In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1β in nARC while circulating, and spleen IL-1β was unaltered. Conclusion: During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1β in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia.

Ghrelin Gene Products in Acute and Chronic Inflammation

“…Total and acylated ghrelin are similar to controls in adult patients with the disease, whereas interestingly, obestatin correlated with some inflammatory markers, in particular TNF-a and IL-6 (Koca et al 2008). In agreement with these findings, increased circulating ghrelin levels and higher mRNA expression in the arcuate nucleus were recorded in rats with adjuvant arthritis, which is similar to human rheumatoid arthritis (Skurlova et al 2010;Stofkova et al 2009). Higher ghrelin levels were also reported in ANCA-associated vasculitis with a direct association with the severity of the disease (Kümpers et al 2008).…”

Cachexia – The Interplay Between the Immune System, Brain Control and Metabolism

“…Most studies agree that during inflammatory anorexia-cachexia syndrome ghrelin levels are upregulated while leptin down-regulated, but food intake is not increased (Laviano et al, 2008). Our studies have shown that rats with chronic inflammatory arthritis associated with anorexia had increased ghrelin and decreased leptin plasma levels along with overexpression of orexigenic neuropeptide (NPY, AgRP) mRNAs and decreased mRNA expressions of anorexigenic neuropeptide CART in the ARC (Stofkova et al, 2009b. However, we did not observe any improvement in food intake or body mass in this chronic inflammatory condition (Stofkova et al, 2009b;.…”

“…Our studies have shown that rats with chronic inflammatory arthritis associated with anorexia had increased ghrelin and decreased leptin plasma levels along with overexpression of orexigenic neuropeptide (NPY, AgRP) mRNAs and decreased mRNA expressions of anorexigenic neuropeptide CART in the ARC (Stofkova et al, 2009b. However, we did not observe any improvement in food intake or body mass in this chronic inflammatory condition (Stofkova et al, 2009b;. Similar situation has occurred in tumor-bearing rats with anorexia-cachexia syndrome.…”

“…Increased expression of pro-inflammatory cytokines in the brain has also been reported in experimental models of chronic diseases associated with anorexia including colitis (El-Haj et al, 2002;K. Wang et al, 2010), cancer (Plata-Salaman et al, 1998) and arthritis (Stofkova et al, 2009b). Yet, there are some contradictory findings showing no differences in brain cytokine (IL-1 , IL-6, TNF-) protein expressions among tumor-bearing mice with prostanoid-related anorexia and their pair-fed controls (W. Wang et al, 2001).…”

Alterations in adipocyte glucose transporter GLUT4 and circulating adiponectin and visfatin in rat adjuvant induced arthritis

“…It is characterized by a number of changes occurring in human RA. In Lewis arthritic rats from day 12 onwards the loss of appetite is accompanied by reduction in plasma levels of leptin, adiponectin, and also by downregulation of the negative reactant of acute phase protein, albumin (Stofkova et al 2009). Similarly, in the same strain of rats from day 21 through 28 of AA, an overall oxidative stress has been observed (Mihalova et al 2007;Strosova et al 2008).…”