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Endocrinology, doi:10.1210/en.2007-1708
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Endocrinology Vol. 149, No. 9 4534-4543
Copyright © 2008 by The Endocrine Society

Central Resistin Regulates Hypothalamic and Peripheral Lipid Metabolism in a Nutritional-Dependent Fashion

María J. Vázquez1, C. Ruth González1, Luis Varela, Ricardo Lage, Sulay Tovar, Susana Sangiao-Alvarellos, Lynda M. Williams, Antonio Vidal-Puig, Rubén Nogueiras, Miguel López and Carlos Diéguez

Department of Physiology (M.J.V., C.R.G., L.V., R.L., S.T., S.S.-A., R.N., M.L., C.D.), School of Medicine, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) (M.J.V., C.R.G., L.V., R.L., S.T., R.N., M.L., C.D.), Spain; Obesity and Metabolic Health Division (L.M.W.), Rowett Research Institute, Aberdeen AB21 95B, United Kingdom; and Institute of Metabolic Science (A.V.-P.), Metabolic Research Laboratories, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom

Address all correspondence and requests for reprints to: Miguel López, Ph.D., and Professor Carlos Diéguez, M.D., Ph.D., Department of Physiology, School of Medicine, University of Santiago de Compostela and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), S. Francisco s/n, 15782, Santiago de Compostela (A Coruña), Spain. E-mail: miguellp{at}usc.es or m.lopez{at}usc.es (M.L.) and fscadigo{at}usc.es or carlos.dieguez{at}usc.es (C.D.).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE HYPOTHALAMUS is a specialized area of the brain consisting of anatomically defined neuronal clusters, or nuclei, that integrate the control of energy homeostasis. Hypothalamic nuclei form interconnected neuronal circuits via axonal projections. The classic theory of feeding control hypothesizes that these nuclei directly respond to changes in energy status by altering the expression of specific neurotransmitters/neuromodulators, which results in changes in energy intake and expenditure (1, 2, 3, 4, 5). Furthermore, current evidence strongly suggests that hypothalamic metabolic pathways, such as fatty acid metabolism, also play a major role in feeding control, by integrating both peripheral stimuli and neuropeptide signaling (6, 7, 8, 9).

Despite considerable progress in identifying the central circuits involved in the regulation of feeding, the mechanism by which energy status is initially sensed by hypothalamic neurons is not completely understood. It is well established that circulating hormones, such as insulin (10), leptin (11), ghrelin (12, 13), peptide YY (14), glucocorticoids (15), and estrogens (16) act on the hypothalamus communicating the status of peripheral energy homeostasis. However, the emergence of new peripheral hormones, such as resistin (RSTN), provide novel candidate signals to fine tune the central response to specific metabolic situations (17, 18).

RSTN, also known as found in inflammatory zone 3 (FIZZ3) is an adipocyte-derived hormone known to promote insulin resistance, impair adipocyte differentiation and promote inflammation (19, 20, 21, 22, 23, 24, 25, 26). In a similar manner to other adipocytokines, RSTN expression is markedly affected by nutritional and metabolic status, with food deprivation leading to a decrease in RSTN mRNA expression (21, 27, 28), whereas circulating RSTN is increased in obese insulin resistant rodents (21) and humans (29, 30). Despite adipose tissue being the more relevant source of RSTN, it has been recently reported that RSTN is also expressed in the hypothalamus (31) and has the capacity to activate hypothalamic neurons in vitro (32). Interestingly, central RSTN administration appears to have a dual effect on metabolic homeostasis, on one hand by acutely inhibiting feeding (33) and on the other by controlling glucose homeostasis and inducing hepatic insulin resistance (17, 18). However, the mechanisms underlying the hypothalamic actions of RSTN are not fully established.

The aim of this study is to characterize the effect of acute and chronic resistin administration on food intake, as well as to uncover any effect on the expression of neuropeptides known to play a major role in the regulation of feeding. Furthermore, we investigated the effects of central RSTN administration in the regulation of lipid metabolism at central (hypothalamus) and peripheral [liver and white adipose tissue (WAT)] levels. Our results indicate that the anorectic effect of RSTN is associated with marked changes in the level of neuropeptide gene expression, namely agouti-related protein (AgRP), neuropeptide Y (NPY), and cocaine and amphetamine-regulated transcript (CART), as well as changes in the hypothalamic expression of enzymes involved in fatty acid metabolism. Additionally, we also demonstrate nutrition-dependent effects of chronic RSTN administration on hepatic and adipose lipid metabolism and proinflammatory cytokines.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Sprague Dawley rats (300–350 g) were housed in a temperature-controlled room, with a 12-h light, 12-h dark cycle (lights from 0800 to 2000 h). The experiments were performed in agreement with the International Law on Animal Experimentation and the experimental protocols have been approved by the Ethics Committee of the University of Santiago de Compostela.

Implantation of intracerebroventricular (ICV) cannulae
Chronic ICV cannulae were implanted under ketamine/xylazine anesthesia as previously described (9, 13, 34, 35). The correct location of the cannula in the lateral ventricle was confirmed by methylene blue staining. Animals were individually caged and allowed to recover for 1 wk before experiment. During the postoperative recovery period, the rats were handled regularly under nonstressful conditions.

Acute RSTN treatment
One group of rats was fed ad libitum, and the other group was deprived of food for 12 h (nocturnal fasting). Rats then received either a single ICV injection of RSTN (Phoenix Pharmaceuticals Inc., Karlsruhe, Germany; 10 µg/rat dissolved in 5 µl of saline) or vehicle. The rats were killed 1.5 h after injection. During the treatment period, both fed and previously fasted (refed) rats received food ad libitum. Treatments started at 0800 h and were carried out in the light phase.

Chronic RSTN treatment
Brain infusion cannulae were stereotaxically placed into the lateral ventricle as described above. A catheter tube was connected from the brain infusion cannula to an osmotic mini-pump flow moderator (model 2001D or 2ML2; Alza Corp., Palo Alto, CA). A sc pocket on the dorsal surface of the animal was created using blunt dissection, and the osmotic mini-pump was inserted. The incision was closed with sutures, and the rats were kept warm until fully recovered. The rats were then infused with either vehicle or RSTN (10 µg/d) for 6 d. On d 4, one group of rats was fed ad libitum, and the other group was deprived of food for the final 48 h of RSTN treatment.

Levels of plasma hormones
Plasma leptin levels were measured by RIA as described previously (9, 13, 34, 35) using reagents provided in commercial kits (Rat leptin RIA, Linco Research Inc., St. Charles, MO).

Real-time quantitative PCR
The mRNA levels of acetyl-coenzyme A carboxylase (ACC) {alpha}, fatty acid synthase (FAS), IL-6, lipoprotein lipase (LPL), stearoyl coenzyme-A desaturase-1 (SCD-1), sterol response element-binding protein-1c (SREBP-1c) and TNF{alpha} in liver and epididymal WAT were studied by using real-time PCR (TaqMan; Applied Biosystems, Foster City, CA) by using specific primers and probes (supplemental Table 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http:// endo.endojournals.org) as previously described (35, 36). All reactions were carried out using the following cycling parameters: 50 C for 2 min, 95 C for 10 min followed by 40 cycles of 95 C for 15 sec, 60 C for 1 min (35, 36). For the analysis of the data, the input value of the gene of interest was standardized to the 18S value for the sample group and was expressed compared with the average value for the vehicle-treated group. We used six to eight rats per group.

In situ hybridization
Coronal brain sections (16 µm) were probed with specific antisense oligo against AgRP, CART, FAS, NPY, melanin-concentrating hormone (MCH), orexin (OX) and proopiomelanocortin (POMC) mRNAs (supplemental Table 2). Suppressor of cytokine signaling-3 (SOCS-3) mRNA levels were quantified using a previously described riboprobe (37). In situ hybridizations were performed as previously published (9, 13, 34, 35, 38, 39). For the in situ analysis we used between seven and 10 animals per experimental group. We used between 16 and 20 sections for each animal (four to five slides with four sections per slide). The mean of these 16–20 values was used as the final densitometry value for each animal.

Western blotting
Hypothalamic total protein lysates were subjected to SDS-PAGE, electrotransferred on a polyvinylidene fluoride membrane and probed with the indicated antibodies: ACC, pACC-Ser79, AMPK{alpha}1 and AMPK{alpha}2 (Upstate, Lake Placid, NY); FAS (BD Transduction Laboratories, Franklin Lakes, NJ), pAMPK{alpha}-Thr172 (Cell Signaling, Danvers, MA); β-actin (Abcam, Cambridge, UK). For protein detection we used horseradish peroxidase-conjugated secondary antibodies and chemiluminescence (Amersham Biosciences, Little Chalfont, UK) (9, 35). We used eight to 12 rats per group and the protein levels were normalized to β-actin for each sample.

Carnitine palmitoyltransferase 1 (CPT1) activity assay
The CPT1 activity was measured in the supernatant, using methods described by López et al. (9), Bieber et al. (40), and Zammit and Newsholm (41). The reaction mixture was composed of 60 mM of Tris HCl at pH 8.0, 1.5 mM of EDTA with 0.05% Triton X-100 and 0.25 mM 5,5'-dithiobis (2-nitrobenzoic acid), and 1.67 mM of carnitine. A total of 100 µl of supernatant and the substrates 5,5'-dithiobis (2-nitrobenzoic acid) and carnitine were added immediately before the measurement of the enzyme activity. The reaction was started by the addition of 0.025 mM of palmitoyl-coenzyme A (palmitoyl-CoA). The increase in absorbance at 412 nm was followed for 5 min. We used eight to 10 rats per group.

Statistical analysis
Data were expressed as mean ± SEM. Statistic significance was determined by ANOVA and post hoc Bonferroni test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Central acute administration of RSTN reduces food intake and induces SOCS-3 expression in the mediobasal hypothalamus
Central (ICV) administration of RSTN to both fed and previously overnight fasted (and subsequently refed) rats markedly decreased food intake (Fig. 1AGo). Because it has been reported that RSTN induced the expression of SOCS-3 in peripheral tissues (17, 42, 43, 44), we evaluated whether similar mechanism may operate in the hypothalamus upon stimulation with RSTN. Our data showed that RSTN markedly increased the expression of SOCS-3 in the mediobasal hypothalamus of fed and fasted rats, particularly in the ependymal layer of the third ventricle, the dorsomedial (DMH) and the arcuate nuclei (ARC) (Fig. 1BGo). Interestingly, changes in SOCS-3 were not associated to altered plasma levels of leptin (Fig. 1CGo), suggesting the existence of a direct RSTN effect. Overall, these data suggest that the anorectic effect of RSTN could be mediated through specific actions on the DMH and ARC nuclei.


Figure 1
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  		FIG. 1. Effect of central acute administration of RSTN on food intake and SOCS-3 mRNA expression. Food intake in fed and refed rats (A) expression of SOCS-3 mRNA in mediobasal hypothalamus (B) and plasma leptin levels (C) after central acute (1.5 h) RSTN administration. n = 7–12 rats per group; **, P < 0.01 vs. Fed vehicle; ***, P < 0.001 vs. Fed vehicle; ###, P < 0.001 Refed vehicle vs. Refed RSTN.

 
Central acute administration of RSTN prevents the fasting-induced physiological effects on AgRP, NPY, and CART mRNA expression
Central acute administration of RSTN did not exert any effect on the mRNA expression of ARC neuropeptides in the fed state. However, when given to fasted rats, RSTN blunted the expected increase in the mRNA expression of AgRP and NPY and the predicted decrease in the gene expression of CART (Fig. 2Go, A–C). Of note RSTN administration did not have any effect on the mRNA expression of POMC, which is coexpressed with CART in the ARC (Fig. 2DGo). Moreover central acute RSTN administration did not have any effect on the mRNA levels of MCH and OX in the lateral hypothalamic area (LHA) (Fig. 3Go, A and B). Overall, these data suggest that the anorectic actions of RSTN on refeeding may be mediated by specific regulation of AgRP/ NPY- and CART-expressing neurons.


Figure 2
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  		FIG. 2. Effect of central acute administration of RSTN on the mRNA expression of ARC neuropeptides. Expression (upper, x5; lower, x20). of AgRP (A), NPY (B), CART (C) and POMC (D) in the ARC of fed and fasted rats after central acute (1.5 h) RSTN administration. n = 7–10 rats per group; **, P < 0.01 vs. Fed vehicle; ***, P < 0.001 vs. Fed vehicle; ##, P < 0.01 Fast vehicle vs. Fast RSTN; ###, P < 0.001 Fast vehicle vs. Fast RSTN. 3V, Third ventricle.

 

Figure 3
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  		FIG. 3. Effect of central acute administration of RSTN on the mRNA expression of LHA neuropeptides. Expression (5X) of MCH (A) and OX (B) in the LHA of fed and fasted rats after central acute (1.5 h) RSTN administration. n = 7–10 rats per group.

 
Central acute administration of RSTN regulates hypothalamic fatty acid metabolism
Central acute RSTN administration stimulated the phosphorylation of AMPK and ACC in fed state. Of interest no specific effect was detected in fasted rats, which exhibited the expected increase in the phosphorylation of both enzymes (Fig. 4Go, A and B). These results indicate that resistin may decrease de novo fatty acid synthesis in the hypothalamus recapitulating the effects observed in the fasted state. In agreement with these data, our in situ hybridization showed that RSTN administration decreased FAS mRNA levels in the ventromedial nucleus of the hypothalamus (VMH) (Fig. 4Go, C and D).


Figure 4
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  		FIG. 4. Effect of central acute administration of RSTN on hypothalamic fatty acid metabolism. Hypothalamic protein levels of pAMPK, AMPK{alpha}1, AMPK{alpha}2, pACC, ACC{alpha}, and ACCβ (A and B) and FAS mRNA levels in the VMH (C and D) of fed and fasted rats after central acute (1.5 h) RSTN administration. n = 7–12 rats per group; *, P < 0.05 vs. Fed vehicle; **, P < 0.01 vs. Fed vehicle; ***, P < 0.001 vs. Fed vehicle. 3V, Third ventricle.

 
Central acute administration of RSTN does not regulate peripheral fatty acid metabolism
Central acute RSTN administration induce no changes in the mRNA expression of ACC{alpha} and FAS either in liver (Fig. 5Go, A and B) or WAT (Fig. 5Go, C and D), suggesting that peripheral fatty acid metabolism is not regulated by central acute RSTN treatment.


Figure 5
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  		FIG. 5. Effect of central acute administration of RSTN on hepatic and WAT lipid metabolism enzymes. Expression of ACC{alpha} and FAS in the liver (A and B) and WAT (C and D) of fed and fasted rats after central acute RSTN administration. n = 6–8 rats per group; *, P < 0.05 vs. Fed vehicle; **, P < 0.01 vs. Fed vehicle.

 
Central chronic administration of RSTN reduces food intake and body weight
Given the profound anorectic effect induced by short-term RSTN administration, we next evaluated whether chronic central RSTN administration by osmotic mini-pumps had any effect on feeding behavior or body weight. Our data showed that RSTN decreased body weight (Fig. 6AGo) and food intake in fed rats (Fig. 6CGo). In addition to the effects of RSTN in rats fed ad libitum, we also assessed the effects of chronic central RSTN infusion on fasted rats, as RSTN levels are markedly suppressed during fasting (21, 27, 28). Our results showed that RSTN-treated fasted rats did not show any additional decrease in body weight when compared with vehicle-treated fasted rats (Fig. 6BGo).


Figure 6
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  		FIG. 6. Effect of central chronic administration of RSTN on body weight and food intake. Body weight change of fed and fasted rats (A and B) and food intake (C) of fed rats receiving chronic ICV RSTN administration for 6 d. Fasted group received food ad libitum during the first 4 d but were starved for the last 48 h of treatment. n = 6–8 rats per group; *, P < 0.05 vs. Fed vehicle. Note that 1) in Fig. 6Go, A and B, x-axis starts on treatment d 2 because on d 1 (first day of treatment) there was no body weight gain in any of the groups; and 2) food intake decreased on d 2 as a consequence of surgery and minipump’s insertion.

 
Central chronic administration of RSTN induces fatty acid synthesis in the liver of fed rats
Central chronic administration of RSTN was associated with a marked increase in the expression levels of LPL, ACC{alpha}, FAS, and SCD-1 in the liver of fed rats (Fig. 7Go, A–D), indicating an overall activation of triglycerides uptake from plasma and fatty acid synthesis in this organ. Consistent with those changes, there was a marked increase in the expression of SREBP-1c (Fig. 7EGo), a transcription factor regulating the expression of lipogenic enzymes (45, 46). On the other hand, central chronic RSTN treatment did not induce any further change in the fasting-induced increase of LPL and the fasting-induced decrease in hepatic lipogenic enzymes and SREBP-1c (Fig. 7Go, A–E). We also observed that CPT1 activity was inhibited in the liver of RSTN-treated rats (Fig. 7FGo), which indicates reduced β-oxidation rate. This effect probably was related to the RSTN-induced increase in ACC{alpha} expression and subsequent boost in malonyl-CoA levels. Finally, to check the possible implication of proinflammatory cytokines as a mediator of the hepatic insulin resistance induced by central RSTN treatment, we studied the expression of IL-6 and TNF{alpha} in the livers central RSTN-treated animals. Our data showed that both cytokines were increased in the liver of RSTN-treated rats (Fig. 7Go, G and H).


Figure 7
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  		FIG. 7. Effect of central chronic administration of RSTN on hepatic lipid metabolism enzymes and proinflammatory cytokines. Expression of LPL (A), ACC{alpha} (B), FAS (C), SCD-1 (D), SREBP-1c (E), IL-6 (G) and TNF{alpha} (H) and CPT1 activity (F) in the liver of fed and fasted rats after central chronic (6 d) RSTN administration. n = 6–8 rats per group for mRNA analysis and 8–10 rats per group for activity assay; *, P < 0.05 vs. Fed vehicle; **, P < 0.01 vs. Fed vehicle; ***, P < 0.001 vs. Fed vehicle.

 
Central chronic administration of RSTN induced fatty acid synthesis in the WAT of fasted rats
In contrast to liver, central RSTN treatment induced a marked increase in the expression levels of LPL, ACC{alpha}, FAS, SCD-1, and SREBP-1c in the WAT of fasted (but not fed) rats (Fig. 8Go, A–E), indicating an overall activation of triglycerides uptake and fatty acid synthesis in this organ under these fasting conditions. Similarly to the liver, CPT1 activity was inhibited in the WAT of RSTN-treated fed rats and was unchanged in RSTN-treated fasted rats (Fig. 8FGo).


Figure 8
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  		FIG. 8. Effect of central chronic administration of RSTN on WAT lipid metabolism enzymes. Expression of LPL (A), ACC{alpha} (B), FAS (C), SCD-1 (D), and SREBP-1c (E) and CPT1 activity (F) in the WAT of fed and fasted rats after central chronic (6 d) RSTN administration. n = 6–8 rats per group for mRNA analysis and eight to 10 rats per group for activity assay; *, P < 0.05 vs. Fed vehicle; **, P < 0.01 vs. Fed vehicle; ***, P < 0.001 vs. Fed vehicle; #, P < 0.05 Fast vehicle vs. Fast RSTN; ##, P < 0.01 Fast vehicle vs. Fast RSTN.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we report that central administration of RSTN exerts anorexigenic effects and influences lipid metabolism in a tissue-specific fashion. Specifically, we show that the anorectic effect of RSTN is associated with marked nutrition-dependent changes in the mRNA levels of AgRP, NPY, CART, and FAS in the hypothalamus. In addition, we demonstrate that chronic central administration of RSTN reduces body weight and activates de novo lipogenesis enzymes in both liver and WAT, in a nutrition-dependent manner.

Although RSTN was initially suggested to promote insulin resistance and adipocyte differentiation, recent data indicate that this hormone also plays a pleiotropic role in rodents, regulating inflammation and reproductive function (21, 22, 23, 24, 25, 26, 47). Besides these direct actions in the periphery, the fact that RSTN is expressed in the central nervous system has renewed the interest in this protein. It is noteworthy that RSTN has been recently reported to act in the hypothalamus, displaying a transient but robust anorectic effect, which has been associated with the short-term feeding control (33). Despite this evidence, the molecular mechanisms underlying the effects of RSTN have remained elusive. The current study suggests that the anorectic effect of RSTN may be mediated via specific actions on the ARC and the VMH. Because it is well established that the ARC is the hypothalamic master-regulator of feeding (1, 2, 3, 4, 5, 48), we first examined the effect of central acute RSTN administration on the mRNA expression of ARC-derived neuropeptides. Our data show that RSTN treatment to prefasted rats prevents the physiological increase in the mRNA levels of orexigenic neuropeptides, specifically AgRP and NPY and a striking increase in the mRNA levels of the anorexigenic neuropeptide CART, which could explain its potent food-reducing effect in refed rats. Our data are somewhat contradictory to the results of a recent report indicating that central RSTN increased NPY mRNA levels in the hypothalamus (18). Those differences may be explained by the different animal models used: in the previous report mice were used, whereas we used rats and also by the way animals were handled after RSTN administration. Moreover, because the receptor mediating the effects of RSTN is still awaiting characterization, it is not possible at present to assess the molecular events involved in RSTN-receptor activation. Further work, assessing the effects of RSTN on animals with specific deletions of genes encoding these neuropeptides should answer this question. Finally, it is important to confirm whether the RSTN-induced changes in mRNA expression correlate with neuropeptide protein levels. It has been recently reported that POMC altered gene expression is not always linked to specific changes in {alpha}-MSH hypothalamic protein content (49). Further work, using HPLC combined with RIA or proteomic analysis, ideally on tissues isolated by laser capture microdissection (50), will help to clarify these issues.

Despite the fact that neuropeptide data in refed rats correlate well with the anorectic effects of RSTN, the lack of effect in fed animals is paradoxical. Central acute RSTN-treated fed rats showed a slight decrease in food intake, but no differences in the gene expression of hypothalamic neuropeptides. Interestingly, our data show that central acute RSTN treatment decreases FAS mRNA expression in the VMH of fed rats. Because recent evidence indicates that the regulation of FAS in the VMH is a physiological key mechanism regulating feeding, integrating peripheral signals, such as ghrelin (9), and pharmacological (35) and genetic inhibition (39) of FAS in this nucleus decreases feeding, our current results suggest that the anorexigenic action of RSTN could also be mediated by specific inhibition of FAS expression in the VMH of fed rats. The lack of effect of RSTN on FAS expression in fasted rats is probably related to the already reduced FAS expression in these animals (9, 35, 39).

In addition to FAS, recent data have also implicated hypothalamic AMPK and its downstream target ACC in feeding control, by integrating peripheral signals, such as adiponectin and leptin, with neuropeptide systems (51, 52, 53). The activity of ACC is allosterically regulated by phosphorylation by AMPK. Activated AMPK phosphorylates and inhibits ACC, thereby reducing flux of substrates in the hypothalamic fatty acid biosynthetic pathway, which increases food intake (51, 54). Because RSTN inhibits AMPK in liver (54), we investigated the effect of central RSTN administration on AMPK/ACC system. Our data show that RSTN induces a marked activation of AMPK and a consequent inactivation of ACC in the hypothalamus. Given the anorectic effect of RSTN and the inactivation of hepatic AMPK after RSTN treatment (54), these results may appear contradictory; however, differing effects on AMPK have been also described for leptin in the hypothalamus (51) and the periphery (55). The reasons for this discrepancy are intriguing. We propose that inactivation of ACC, after AMPK activation, may be a physiological compensatory mechanism that prevents deleteriously high levels of malonyl-CoA occurring in the hypothalamus after FAS inhibition in the VMH (9, 35, 39). This mechanism might also explain the transient anorectic effect of central RSTN (33). Supporting this hypothesis, hypothalamic CPT1 activity does not change in RSTN-treated fed rats within the same time frame (data not shown), suggesting that malonyl-CoA levels are unchanged, as a consequence of ACC inactivation.

Next, we evaluated the effect of chronic RSTN administration on body weight and food intake. Our data showed that long-term RSTN treatment displayed a mild anorectic effect when compared with acute administration. We have previously reported that anorectic effect of acute RSTN administration displays a marked circadian effect, being maximal at the beginning of the light cycle (33). In the present study, acute RSTN treatment was carried out exactly in the same time-frame as in the former study. On the other hand, the chronic administration protocol was based on osmotic minipumps, which tonically released RSTN (1 µl/h) throughout the treatment time; thus, we speculate that this constant release may blunt or at least dilute the presence of any circadian effect, which would explain the mild action of chronic RSTN on food intake.

Current data suggests that nutritional and hormonal signals control peripheral glucose and lipid metabolism through a dual mechanism involving direct actions on those tissues, as well as hypothalamic-mediated effects (56, 57, 58, 59, 60). Thus, we evaluated the effects of central chronic RSTN administration on hepatic and WAT lipid metabolism. Our data showed that central RSTN induced the expression of fat-promoting enzymes in both tissues in a nutrition-dependent fashion, being increased in the liver of fed and in the adipose tissue of fasted rats. The physiological significance of this effect is intriguing. Impaired lipid metabolism is one of the well-defined characteristics of insulin resistance and can affect gene expression and intracellular signaling pathways, thus leading to energy imbalance, abnormal insulin action, and metabolic syndrome (61, 62, 63). Moreover, triglycerides, free fatty acids, and cholesterol have all been demonstrated as crucial players in the development of inflammatory responses and insulin resistance (61, 62, 63). Consequently, the RSTN-induced changes in enzymes involved in regulating triglyceride uptake and lipid metabolism, such as LPL, ACC, FAS, and SCD-1, as well as key transcriptional factors regulating lipid metabolism, such as SREBP-1c and proinflammatory cytokines, such as IL-6 and TNF{alpha}, are likely to be linked to the altered insulin sensitivity observed after RSTN administration (17, 18). Recent data point to the fact that central RSTN induces hepatic insulin resistance by increasing the expression of proinflammatory cytokines, such as IL-6 and TNF{alpha}, via an unidentified mechanism mediated by the autonomic nervous system (17, 18) and that alterations in proinflamatory adipocytokines may be due, in part, to the excess accumulation of fatty acids and triglycerides in the liver after central treatment with RSTN.

Finally, we investigated the effect of central chronic RSTN on lipid metabolism in WAT. Unlike the liver, triglyceride uptake and enzymes involved in de novo lipogenesis were not modified in the WAT of RSTN-treated fed rats, indicating that central RSTN modulates the expression of lipogenic enzymes in the periphery in a tissue-specific manner. However, as in the liver, central RSTN decreased WAT CPT1 activity, suggesting that central RSTN decreases lipid mobilization in both liver and WAT. Interestingly, triglyceride uptake and expression of de novo fatty acid synthesis enzymes were increased by RSTN in WAT in the fasted state. The physiological relevance of these data are very intriguing. Considering that food deprivation leads to a decrease in RSTN levels (21), in parallel to inhibition of the lipogenic program in WAT (45, 46), our results suggest that central RSTN directly acts on the hypothalamus as a signal mimicking the fed state to promote fat deposition. Thus, we hypothesize that RSTN supplementation to fasted animals is enough to mimic the effect of fed state on overall activation of lipid uptake and anabolism, which makes central RSTN a unique dual-action molecule: anabolic in the periphery and anorectic in the hypothalamus. Further work will be necessary to address this issue.

In summary, our data demonstrate that RSTN regulates food intake and body weight in rodents. This anorectic action involves the activation of hypothalamic AMPK and inactivation of enzymatic steps of de novo fatty acid biosynthetic pathway, namely ACC and FAS, as well as the regulation of gene expression of NPY, AgRP, and CART in the ARC. Furthermore, our data suggest that when hypothalamic RSTN activity is increased a coordinate response elicits a shift in substrate utilization and nutrient partitioning to ultimately promote fat storage by increasing the lipid synthesis in liver and WAT. The increased fat deposition might at least partially explain the central RSTN-induced insulin resistance, probably through a proinflammatory mechanism involving IL-6 and TNF.

Understanding how central RSTN circuits control fat storage and metabolism could provide another important step in unraveling the interactions between the hypothalamus, adipocytokines, and periphery, which will improve our understanding of metabolic syndrome and obesity.


   Footnotes
 
This work has been supported by grants from Xunta de Galicia (to M.L.: GRC2006/66), Fondo Investigationes Sanitarias (to M.L.: PI061700), Spanish Ministry of Education and Science (to M.E.C. and C.D.: BFU2005), Mútua Madrileña (to C.D. and M.L.), Medical Research Council (MRC; to A.V.P.), Scottish Government Rural and Environment Research and Analysis Directorate (RERAD; to L.M.W.) and European Union (to C.D.: LSHM-CT-2003-503041, Diabesity http://www.eurodiabesity.org and to A.V.P.: LSHM-CT-2005-018734: Hepadip, http://www.hepadip.org). R.N. is currently recipient of a Marie Curie Outgoing International Fellowship. CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII.

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 22, 2008

1 M.J.V. and C.R.G. have equally contributed to this work. Back

Abbreviations: ACC, Acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus of the hypothalamus; AgRP, agouti-related protein; CART, cocaine and amphetamine-regulated transcrip; CoA, coenzyme A; DMH, dorsomedial; FAS, fatty acid synthase; CPT1, carnitine palmitoyltransferase 1; ICV, intracerebroventricular; LHA, lateral hypothalamic area; LPL, lipoprotein lipase; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; OX, orexin; POMC, proopiomelanocortin; RSTN, resistin; SCD-1, stearoyl coenzyme-A desaturase-1; SOCS-3, suppressor of cytokine signaling-3; VMH, ventromedial nucleus of the hypothalamus.

Received December 11, 2007.

Accepted for publication May 15, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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