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Department of Physiology, University of California, San Francisco, San Francisco, California 94143
Address all correspondence and requests for reprints to: Dr. James Warne, Department of Physiology, Box 0444, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143. E-mail: james.warne{at}ucsf.edu.
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Introduction |
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When there is a choice of caloric sources (chow and lard), B induces an increase in total caloric intake, whereas the choice of what calories are derived from which food source is strongly influenced by the prevailing insulin levels (6). In adrenalectomized rats, B replacement produces a dose-dependent increase in lard, but not chow, intake whereas in adrenalectomized rats with streptozotocin (STZ)-diabetes, B replacement produces a dose-dependent increase in chow, but not lard, intake. Lard intake is restored in the STZ-treated rats in a dose-dependent fashion by increasing circulating insulin levels (6). Furthermore, in STZ-diabetic rats with moderately elevated B concentrations, venous insulin replacement results in the exclusive recovery of lard, but not sucrose, intake with consequent inhibition of chow intake, when all three sources of calories are offered ad libitum (7). Low concentrations of insulin secreted in anticipation of meals have also been shown to increase ingestion of palatable but noncaloric foods in humans (8). Venous insulin replacement into the superior mesenteric and right external jugular veins both restore voluntary lard intake in STZ-diabetic rodents. However, because superior mesenteric insulin infusions more naturally replace insulin of pancreatic origin and also do not necessarily result in significantly elevated insulin levels in the systemic circulation, despite having clear actions on hepatic glucose metabolism, these data pointed to the liver as a key regulatory site for lard intake (7).
There is clear and reciprocal communication between the brain, notably the hypothalamus, and the liver that regulates many key aspects of metabolism (9). For example, insulin acting on the central nervous system (CNS) can regulate hepatic glucose output through vagally mediated suppression of gluconeogenesis (10). However, afferent signals from the liver can affect the brain regulation of energy homeostasis as well. For example, inhibition of fatty acid oxidation by mercaptoacetate increases food intake (11), an effect that is most likely triggered by a signal from the liver because the effects of mercaptoacetate are abolished by hepatic branch vagotomy (HV) (12). HV also prevents the lard-induced inhibition of food intake and changes in neuropeptide expression in STZ-diabetic rats (13, 14). Because the liver is a major target organ for insulin, which inhibits glycogenolysis and gluconeogenesis, and promotes fat synthesis (15), there is therefore major potential for an insulin-stimulated generation of metabolic signals to affect hepatic vagal afferents and, consequently, affect food intake.
In these studies, we assessed the contribution of an insulin-stimulated, hepatic vagus-derived signal in mediating voluntary lard ingestion in STZ-diabetic, B-clamped rats. Two subdivisions of rats, based on the experimental manipulations, making a total of 10 groups, were examined. The first subdivision consisted of five groups: nondiabetic control, STZ-diabetic with vehicle infused into the jugular (Veh-Jug) or superior mesenteric vein (Veh-Mes), and STZ-diabetic with insulin infused into the jugular (Ins-Jug) or mesenteric vein (Ins-Mes). Each group was then further subdivided into two groups: one was sham HV (sham), and the other underwent HV. At the end of the experiment, plasma and liver samples were taken to confirm levels of B and insulin as well as insulin-sensitive hormones, metabolites, and liver glycogen levels to confirm biological action. White adipose tissue (WAT) depots were excised and weighed to gauge outcomes of lard intake and delineate any differences between the two venous infusion sites, which have been previously shown to have different effects on different WAT depots (7).
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Materials and Methods |
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Surgical procedures and treatments
The experimental design expanded on that previously reported (7), with the same treatment schedule, but in this instance, additional surgical manipulations of the hepatic vagus. There were five rats in each of the 10 groups. All procedures were performed in one surgery (d 0). All rats were anesthetized using ketamine (75 mg/kg, im) and xylazine (10 mg/kg, im). Ketoprofen (10 mg/kg, sc) was provided as an analgesic after surgery but before the rat regaining consciousness. All rats received incisions into the right of the neck for access to the right external jugular vein (catheter inserted if appropriate for that group) as well as the left side of the body for access to the hepatic vagus and, if appropriate, the superior mesenteric vein. During all procedures, the opened abdominal cavity was bathed in sterile saline to prevent drying of the viscera. All rats received a sc pellet of B. After all appropriate surgical manipulations were performed, all incisions were closed using silk suture.
The rats were allowed 5 d to recover after surgery, during which incisions, body weight, and food and water intake were monitored daily at 1000 h. All rats were also presented with lard ad libitum on d 5 at 1000 h. Body weight and solid and liquid intakes were monitored daily for a further 5 d. On d 10 at 1000 h, final day food and water intake measures were taken. All rats were then killed by decapitation and samples were collected.
HV.
The common hepatic vagal branch was visualized through an incision into the left side of the body by gently moving aside surrounding tissues, which were held out of the field of view with saline-soaked sterile gauze. For the HV groups, the common hepatic vagal branch was located as it separates from the left vagal trunk and cut. The sham-operated groups underwent all procedures except transection of the neural tissue (13). The hepatic branch transection was visualized at the end of the experiment. In all HV operated rats, the common hepatic vagal branch was still transected.
STZ-induced diabetes.
Diabetes was induced by a sc injection of STZ [Sigma Chemicals, St. Louis, MO; 65 mg/kg in citrate buffer (pH 4.2)], whereas the rats were still unconscious. Control rats were injected with citrate buffer (2 ml/kg). Diabetes was confirmed by the presence of marked glucosuria (Multistix 9 SG; Bayer Corp., Elkhart, IN) on d 3.
Insulin replacement.
The same, low dose of insulin (3 U/d; Humulin R U500; Eli Lilly and Co., Indianapolis, IL) or saline was infused in the STZ-treated animals at one of two locations (jugular or superior mesenteric veins) via the insertion of catheters (PE5 tubing, 1.5 cm, fused to PE60 tubing, 1.5 cm) attached to osmotic minipumps (Alzet, model 2002; Alza, Palo Alto, CA) as previously described (7). For the jugular infusions, the right external jugular vein was accessed from an incision into the side of the neck. The vein was exposed, gently elevated, a small incision was made and the catheter was inserted. The vein was sealed using sterile glue (Vetabond; 3M Animal Care Products, St. Paul, MN). A sc pocket from the neck to the back was then created to hold the catheter and attached osmotic pump. For the superior mesenteric infusions, the cecum was externalized from the incision made into the left side of the body and placed onto gauze soaked in sterile saline and the superior mesenteric vein was gently exposed. The catheter was inserted into the vein and immediately sealed into place using sterile glue. The cecum and osmotic minipump were then quickly internalized, such that the minipump nestled close to the cecum and small intestine. The presence of an osmotic minipump at either site did not cause any obvious signs of discomfort for the rats.
B treatment.
Circulating B levels were maintained at steady-state concentrations by placing a 100 mg pellet of B (100%; Steraloids Inc., Newport, RI) sc through a small incision in the back. Previous studies have shown this treatment produces sustained moderate elevations (
150 ng/ml) in the concentrations of B (16).
Sample collection.
After rats were killed by decapitation, trunk blood was collected into chilled tubes containing 100 µl EDTA (65 mg/ml). Tubes were centrifuged, plasma collected and stored at –80 C. Liver biopsies (100 mg) were quickly collected from the same lobe (lobus sinister lateralis), snap frozen, and stored at –80 C. The rest of the body was put onto ice for subsequent dissection and weighing of the WAT fat pads [left and right sc (scWAT), epididymal (eWAT), perirenal (pWAT), and mesenteric (mWAT)], thymus, and spleen. At this time, the position of the catheters and osmotic minipumps was verified. In all cases, one end of the catheter was securely inserted into the desired vein, the other attached to the minipump. In addition, the hepatic vagus was visualized and in all cases appeared severed.
Plasma and liver assays.
Plasma B, insulin, leptin, and IGF-I concentrations were assessed by RIAs at half-volumes (MP Biomedicals, Orangeburg, NY; Linco Research Inc., St. Charles, MO; Diagnostic Systems Laboratories Inc., Webster, TX), whereas plasma glucose, triacylglycerols, glycerol, total ketone bodies, and free fatty acids (FFAs) were measured colorimetrically on a plate reader using kits (Mega Diagnostics, Los Angeles, CA; Sigma-Aldrich, St. Louis, MO; Wako Chemicals, Neuss, Germany), all as previously described (6, 7). Liver glycogen content was assessed by a colorimetric plate assay outlined previously (17) and was standardized to milligrams wet weight.
Statistical analyses
All data are presented as the mean ± SE of the mean. Body weight data were analyzed by repeated-measures ANOVA followed by a repeated measures t test to compare HV vs. sham operated for each group.
Due to the nature of the experimental design, all other data were analyzed in two ways. First, the STZ-treated groups (Veh-Mes ± HV, Ins-Mes ± HV, Veh-Jug ± HV, Ins-Jug ± HV) were analyzed by three-way ANOVA to test for significant (P < 0.05) effects of and interactions between the condition of the hepatic vagus (HV vs. sham), insulin replacement (vehicle vs. insulin), and site of replacement (superior mesenteric vs. right external jugular). The results of the three-way ANOVA are summarized in Table 1
. Data from all groups were subsequently analyzed by two-way ANOVA to compare data with nondiabetic, but still moderate B, controls. The factors for this statistical test were condition of the hepatic vagus (HV vs. sham) and insulin manipulation (control, Veh-Mes, Ins-Mes, Veh-Jug, Ins-Jug). Significant (P < 0.05) effects after both three-way and two-way ANOVAs were followed by post hoc tests of individual group differences (Tukey’s test), the results of which are presented on the figures, in which different letters indicate statistically significant differences between groups (e.g. a is different from b, but neither is different from ab).
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. All rats initially lost weight during the study because of the catabolic effects of the moderately elevated B (18). In the sham-operated rats (Fig. 1A), STZ treatment initially further exacerbated this weight loss in all groups except those that received insulin into the jugular vein (P < 0.05). Introduction of lard on d 5 curtailed further weight loss in all groups such that only the Veh-Jug group remained significantly lower (P < 0.05) than the nondiabetic controls. HV curtailed the initial differences between the treatment groups such that no significant differences existed (Fig. 1B).
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) and those rats receiving vehicle into the superior mesenteric vein (Veh-Mes; Fig. 1D) showed no significant differences between the two groups. In contrast, HV attenuated the weight loss on d 2, 3, and 4 of the study in those rats receiving insulin replacement into the superior mesenteric vein, compared with sham-operated counterparts (Ins-Mes; Fig. 1E). The STZ-treated rats that received vehicle into the jugular vein showed significant (P < 0.05) time, treatment, and time-treatment interaction effects (Veh-Jug; Fig. 1F). Specifically, weight loss was greater in the sham-operated, compared with HV, group on d 8, 9, and 10 of the study. Rats receiving insulin into the jugular vein also displayed significant (P < 0.05) time, treatment, and time-treatment interaction effects; however, in this instance the sham-HV operated rats lost less weight than the HV-operated counterparts, with significance evident on d 4 and 5 of the study (Ins-Jug; Fig. 1G).
The effects of HV, STZ-diabetes, and site-specific insulin replacement on caloric intake are shown in Fig. 2. Chow intake during the 5 d of recovery after surgery rose steadily in the STZ-treated groups (data not shown). Provision of lard on d 5 resulted in all groups consuming the new food equally over the chow during the first day of availability. The data presented in Fig. 2 and Table 1 for 5-d food intake reflect consumption from the second day of ad libitum access until the end of the study. Three-way ANOVA of the STZ-treated groups (Table 1) revealed a significant (P < 0.05) effect of insulin and a significant (P < 0.05) insulin-HV surgery interaction, but no effect of the site of venous infusion, on lard intake (Fig. 2A). Subsequent post hoc analysis showed, in those rats receiving superior mesenteric venous infusions, that HV increased lard intake in the saline-infused rats to the level of their insulin-infused counterparts. This amount of lard intake was similar to that observed in the nondiabetic control rats. HV did not modify the effects of venous insulin infusion. Those rats that had jugular venous infusions showed a pattern like that of the superior mesenteric infused rats, with insulin infusion increasing lard intake in the sham HV-operated rats. However, the HV-operated rats with either saline or insulin infusions were not significantly different from the sham-operated, saline-infused rats.
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) and total caloric (Fig. 2C) intake were significantly attenuated by insulin replacement, irrespective of site, in STZ-diabetic rats. Post hoc tests also revealed that chow intake was reduced by HV in the group that received vehicle into the superior mesenteric vein, an effect not evident in the corresponding jugular group that received vehicle infusion. Both chow and total caloric intake were significantly higher (P < 0.05) than that of the nondiabetic controls.
As shown in Fig. 3 and Table 2, STZ-diabetes resulted in a significant reduction (P < 0.05) in the weight of all of the fat pads examined. This effect, however, did not reach statistical significance in the mWAT of the sham-HV operated rats that received vehicle into the superior mesenteric vein, when mWAT weight was adjusted per gram body weight (Fig. 3C). Analysis within the STZ-treated groups of both absolute (Table 2) and body weight-adjusted (Fig. 3) WAT weights by three-way ANOVA revealed several significant (P < 0.05) effects. Left scWAT weight showed a significant (P < 0.05) HV surgery-replacement site interaction. The jugular insulin-induced maintenance of left scWAT weight was attenuated by HV such that it was not significantly different from the STZ-depleted weights of all other groups. In contrast, right scWAT weight was unaffected by any experimental manipulation within the STZ-treated groups.
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), eWAT (Fig. 3D), pWAT (Fig. 3E), and total WAT (Fig. 3F) weights; specific effects of site on mWAT, eWAT, and total WAT; and insulin-site interactions on mWAT and eWAT. Post hoc analysis showed that venous insulin infusion into the superior mesenteric, but not jugular, vein increased mWAT, eWAT, and total WAT weight of both sham HV and HV-operated groups. Insulin infusion into the jugular vein also increased eWAT and total WAT weights in the sham HV, but not HV, group. Insulin into the superior mesenteric and jugular veins attenuated some, but not all, of the STZ-induced loss of pWAT weight, when compared with the nondiabetic controls. Interestingly, saline infusion into the jugular vein of HV operated rats also maintained pWAT weight.
Plasma variables are shown in Table 3 and Fig. 4. STZ-diabetes significantly reduced plasma insulin (Fig. 4A; P < 0.05) and leptin (Fig. 4B; P < 0.05) concentrations and elevated glucose (Fig. 4C; P < 0.05), total ketone bodies (Fig. 4D; P < 0.05), FFAs (Fig. 4E; P < 0.05), triacylglycerol (Fig. 4F; P < 0.05), and glycerol (Table 3; P < 0.05) levels, compared with nondiabetic controls. Three-way ANOVA of the STZ-treated groups (Table 1) revealed significant (P < 0.05) insulin, but not venous, delivery site, effects on plasma insulin, leptin, glucose, and triacylglycerol concentrations. Subsequent post hoc analysis showed in the sham HV groups, that insulin replacement into either site elevated plasma insulin (P < 0.05 for jugular infusion but a nonsignificant trend for mesenteric) and leptin (P < 0.05) levels and significantly reduced (P < 0.05) circulating glucose and triacylglycerol levels without affecting total ketone bodies, FFAs, or glycerol levels. HV did not significantly modify the effects on insulin, FFAs, glycerol, or total ketone bodies. HV did lead to an elevation (P < 0.05) in plasma leptin in the group infused with vehicle into the jugular vein, compared with the sham HV group. Three-way ANOVA also showed a significant (P < 0.05) insulin-HV surgery interaction on plasma glucose levels, with post hoc analysis showing that HV prevented the insulin-induced reduction in circulating triacylglycerol levels when infused into the superior mesenteric, but not jugular, veins. The plasma concentrations of B and IGF-I were unaffected by any of the experimental manipulations (Table 3). There were no significant effects on B-sensitive thymus or spleen weight revealed by three-way or two-way ANOVA after any experimental manipulation (Tables 1 and 3).
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). Insulin replacement at both sites restored liver glycogen content (three-way ANOVA, effect of insulin P < 0.001; Table 1) to that of control, nondiabetic levels. HV had no independent effects on liver glycogen content and did not significantly modify the effects of insulin in STZ-treated rats.
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Discussion |
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All of the data from the sham-HV operated rats confirm our previous observations (7). A key distinction between this and our previous study (7) is that the steady-state levels of B in this experiment were lower, at 0.32 ± 0.02 µM in this experiment, compared with 0.55 ± 0.02 µM previously. This is likely to have influenced the effects of STZ-diabetes on mWAT, such that a slight but nonsignificant reduction was evident in the STZ-diabetic rats that had vehicle replaced into the superior mesenteric vein. The lower, steady-state B levels could also have enabled control, nondiabetic rodents to restore much of the postsurgery body weight loss once the lard was introduced. In addition, in this study circulating insulin levels were raised, although not significantly, after superior mesenteric infusion of insulin, which was not evident before. This insulin elevation is likely to account for the increase in leptin and reduction in triacylglycerol levels evident in this study with superior mesenteric infusion because both are insulin sensitive (19, 20), also suggested by our previous study (7).
The hepatic vagus is a two-way highway of communication between the liver and brain (21), and HV severs both afferent and efferent signaling. Under our experimental conditions, the hepatic vagus clearly exerts an inhibitory influence on lard intake. The hepatic vagus also mediates lard-induced attenuation of STZ-diabetic hyperphagia by enabling restoration of hypothalamic neuropeptide expression (13, 14). HV has also been shown to increase glucose deprivation-induced feeding response to intracerebroventricular 2-deoxyglucose injections (22). Furthermore, visceral afferent signaling appears to inhibit unfamiliar high-fat food consumption (23). Collectively, these studies support our data showing an inhibitory role for the hepatic vagus in aspects of the regulation of food, notably fat intake. HV also severs fibers running to the proximal duodenum (21); hence, the gastrointestinal tract might also play an important role in regulating food intake. Vagal afferents from the duodenum mediate cholecystokinin-induced inhibition of food intake (24). However, gastroduodenal vagotomy does not block the lard-induced reduction in STZ-diabetic hyperphagia as HV does (13), suggesting at least this facet of lard action is dependent on vagal nerves from the liver.
Insulin can clearly overcome the inhibitory signal from the hepatic vagus, resulting in lard intake. This is likely to be a direct effect of insulin, because none of the downstream metabolic variables examined, namely glucose, IGF-I, and total ketone bodies, showed the same pattern of change as that of lard intake with insulin replacement, with the former being previously ruled out in other studies (6, 7). The liver is a possible site of insulin action because an elevation in liver glycogen concomitant with a reduction in plasma glucose was evident. Moreover, elevated circulating insulin levels are not a prerequisite for insulin-induced lard intake provided insulin action is clearly evident in the liver (7). Insulin receptors are also found throughout the brain (25), making direct central insulin action possible. However, intracerebroventricular administration of high insulin concentrations reduces palatable food intake (26), suggesting peripheral, possibly liver, insulin effects are more likely. Central insulin action, however, is likely responsible for the reduction in chow and, by consequence, total food intake, in keeping with its established actions (27).
It is clear that the effects of both HV and insulin on voluntary lard intake are considerably stronger when there is the physical presence of a pump in the body cavity. One distinguishing factor in this regard could be mWAT weight. Comparison of STZ-diabetic, vehicle-infused groups clearly shows that the presence of the minipump in the body cavity selectively increases predominantly mWAT weight, with small effects also on the other intraabdominal WAT depots. It is unclear what is triggering this increase in weight; however, it could be the consequence of a local inflammatory reaction surrounding the minipump. Afferent nerve signals from intraabdominal fat tissue can regulate food intake by modulating hypothalamic leptin sensitivity (28). Hence, greater intraabdominal WAT depot weights could be permissive for lard intake by affecting the hypothalamic regulation of food intake.
The pellet of B used elevated circulating corticosterone concentrations to approximately 2.5 times above the normal 24-h mean daily basal value (16), but was lower than the normal circadian maximum, and was not extreme. Such persistent elevations of this magnitude can occur endogenously during the application of intermittent stressors (29). Moreover, with chronic stressors, insulin concentrations are usually lower than normal, approximating the values found in this study. Thus, our model, which controls both B and insulin, is analogous, in terms of these hormone concentrations, to several models of chronic stress in which the endogenous hormones can freely fluctuate.
We have found in other studies that the free choice between either lard plus chow (30) or choice among lard, 32% sucrose, and chow (31) results in decreased hypothalamus-pituitary-adrenal responses to subsequent restraint and during repeated restraint, respectively. An important consequence of the chronic stress experiments, in which rats are allowed free access to lard alone or to lard plus sucrose, in addition to chow, is that not only do the animals gain mesenteric fat but also there is an inverse and quite strong correlation between mesenteric fat mass and hypothalamic corticotropin-releasing factor, suggesting that a signal, or signals, resulting from such comfort food intake may be stress relieving (18). The results in this study strongly suggest that one signal to the brain that results from eating lard may be mediated by the hepatic branch of the vagus.
The direct outcome of insulin infusion and consequent increased lard ingestion is an increase in total WAT weight and plasma leptin levels. The pattern of WAT accumulation appears to depend on the site of insulin replacement. Insulin into the superior mesenteric vein, so that it takes its normal secretory pathway, favors an increase in mWAT weight, which is unaffected by HV. By contrast, jugular insulin infusions favor an increase in left scWAT weight, as previously observed (7), an effect that is attenuated, albeit nonsignificantly, by HV, in this instance reflecting lard intake. Hence, local insulin effects are likely to be responsible for directing or enabling WAT deposition, with its total weight being dependent on lard ingestion.
Body weight changes after HV have been previously documented to be better than sham-operated controls (13, 32), in keeping with our data. These changes in body weight were not due to changes in circulating IGF-I levels, which were unchanged by any experimental manipulation.
In the sham-HV operated rodents, insulin replacement caused an increase in hepatic glycogen content and reduction in circulating glucose levels, consistent with insulin action to improve the deranged glucose homeostasis of STZ-diabetes. Consistent with previous findings (33), HV did not affect liver glycogen levels. However, HV did prevent the actions of insulin on plasma glucose levels and ablated actions of superior mesenteric, but not jugular, infused insulin on reducing circulating triacylglycerol levels. Intracerebroventricular administration of insulin can, via the vagus, stimulate hepatic IL-6/signal transducer and activator of transcription-3 signaling, resulting in hepatic gluconeogenic gene expression and glucose production (10, 34, 35, 36). Hence, ablation of the efferent vagal signal from the hypothalamus could inhibit the normally suppressive actions of CNS insulin on glucose output from the liver, accounting for our findings.
HV also ablated the actions of superior mesenteric, but not jugular, infused insulin on reducing triacylglycerol levels. Afferent signaling from the hepatic vagus and efferent sympathetic nerves to adipose tissue regulate energy expenditure, glucose metabolism, and fat distribution (37). Because distinct brain regions communicate with distinct fat pads (38), HV might sever a specific liver-brain-intraabdominal fat pad axis. Because mWAT and eWAT are more significantly affected by superior mesenteric insulin than jugular, these are likely to represent the main source of circulating triacylglycerols in these rats, certainly because mWAT has the most rapid turnover of triacylglycerols (39) as well as being more densely innervated (40) and more highly vascularized (41). Hence, HV could interrupt CNS/liver insulin inhibition of triacylglycerol release from or stimulate uptake into mWAT but not scWAT.
In conclusion, these data show that severing the hepatic vagus can influence the choice of food intake, body weight, and metabolism in STZ-diabetic rats and affects the way in which sit-specific insulin replacement rescues some of these to nondiabetic levels. Although the preparation is artificial, the insulin and B levels are analogous to those observed under persistent stressors, and it seems clear that insulin acts via the hepatic branch of the vagus to stimulate lard instead of chow intake, although overall calories are maintained constant. Considering the current obesity epidemic as well as the greater sense that more chronic stressors are associated with our current life and work styles (42, 43, 44, 45), understanding of food intake behavior is of paramount importance. Hence, the hepatic vagus and the peripheral tissues innervated by it are important candidate sites to manipulate food intake behavior.
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Disclosure Statement: The authors have nothing to disclose.
First Published Online April 5, 2007
Abbreviations: B, Corticosterone; CNS, central nervous system; FFA, free fatty acid; eWAT, epididymal WAT; HV, hepatic branch vagotomy; mWAT, mesenteric WAT; pWAT, perirenal WAT; scWAT, subcutaneous WAT; STZ, streptozotocin; WAT, white adipose tissue.
Received January 3, 2007.
Accepted for publication March 26, 2007.
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