Hypothalamic Resistin Immunoreactivity Is Reduced b y Obesity in the Mouse: Co-Localization with α-Melanostimulating Hormone

Abstract

Resistin is a new adipokine expressed in mouse, rat and human adipose tissue. Resistin may be an important link between obesity and insulin resistance, though this controversial view is complicated by the discovery of multiple sites of resistin expression, including human macrophages, placenta and pancreas. In previous studies we demonstrated that the mouse hypothalamo-pituitary system was also a site of resistin production. Pituitary resistin is developmentally regulated, reduced in the ob/ob mouse and severely down-regulated by food deprivation (24 h). An unexpected finding was that hypothalamic resistin mRNA remained unaffected by fasting. The present experiments examined the localization and possible regulation of hypothalamic resistin protein. Using immunohistochemistry we observed a complex network of resistin+ fibres extending rostrally from the arcuate nucleus of the hypothalamus (ARC) to the preoptic area. Labelled cell bodies occurred only in the ARC and in a periventricular region of the dorsal hypothalamus. Hypothalamic resistin immunoreactivity (ir) was unaffected by fasting (48 h) or by a high fat diet, but the periventricular staining was greatly increased in the lactating mouse. Marked reductions in resistin+ fibres were seen in brain tissue from: (a) ob/ob mice, (b) young mice made underweight for their age by raising them in large litters (20 pups per litter) and (c) mice with hypothalamic lesions induced by monosodium glutamate (MSG) or gold thioglucose (GTG). We speculate that the resistin-ir deficit in genetically obese mice, and in severely underweight mice, could be due to low or absent leptin. In contrast, though MSG- and GTG-treated mice have high levels of circulating leptin, in the presence of excessive visceral fat deposits, we hypothesize that damage to the ARC destroys the resistin+ cell bodies. This latter supposition led us to an additional hypothesis, that resistin-ir would be contained in neurons expressing the proopiomelanocortin (POMC) gene. This proved to be correct. Double label immunofluorescence histochemistry revealed that α-MSH-ir, a marker for POMC neurons, was co-localized with resistin-ir. In conclusion, our data reveal a second example of an adipocytokine co-localized with a hypothalamic neuropeptide. We reported previously that leptin was co-localized with oxytocin and vasopressin. RT-PCR analysis confirmed that resistin mRNA is readily detectable in ARC, but further work is required to determine whether the resistin gene is expressed in POMC neurons or if resistin is specifically accumulated by these cells. Nonetheless, our data suggest that the hypothalamus is a target tissue for resistin.

Central administration of resistin promotes short-term satiety in rats

“…The only hypothalamic or forebrain region to show resistininduced Fos protein expression was the arcuate nuclei. These results are in concordance with previous works showing that resistin expression is co-localized with alphamelanostimulating hormone (a-MSH) in the arcuate nucleus (11). Even though Wilkinson et al observed that hypothalamic resistin mRNA remained unaffected by fasting, there was a marked reduction in resistin positive fibres from ob/ob mice and in underweight mice (11).…”

“…However resistin mRNA expression was found in the arcuate nucleus (11) and it remains unknown whether resistin is centrally active or whether it interacts with the hypothalamic circuits that regulate energy balance. The aim of the present study is therefore to seek evidence that resistin is a centrally active peptide participating in the control of energy balance.…”

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…Insulin clamp was performed at 10 -12 weeks of age. Resistin is expressed in the arcuate nucleus and periventricular regions of the dorsal hypothalamus (Wilkinson et al, 2005); hence, clamp studies were also done in C57BL/6J retnϪ/Ϫ mice to ascertain the contribution of locally expressed resistin on glucose metabolism.…”

“…Because resistin is present in the CSF (Kos et al, 2007) and is expressed locally in the hypothalamus (Wilkinson et al, 2005), it is possible the change in insulin sensitivity involves hormonal as well as paracrine mechanisms. Thus, we determined whether centrally administered resistin was still capable of regulating glucose fluxes in the absence of endogenous resistin expression.…”

“…We hypothesized that central resistin administration regulates glucose fluxes through hypothalamic neuropeptides which mediate energy and glucose homeostasis. Furthermore, we distinguished between the effects of intracerebroventricular resistin treatment and local resistin expression in the hypothalamus (Wilkinson et al, 2005) by studying wild-type (WT) and retnϪ/Ϫ mice.…”