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Brain Research Bulletin, Vol. 27, pp. 51 l-515. 0 Pergamon Press pk. 1991. Printed in the U.S.A

Role of the Efferent and Afferent Vagus Nerve in the Development of Ventromedial Hypothalamic (VMH) Obesity SHUJI INOUE,’ HAJIME NAGASE, SHINOBU SATOH, MAR1 SAITO, MASATO EGAWA, KATSUAKI TANAKA AND YUTARO TAKAMURA The Third Department

ofInternal

Medicine,

Yokohama City University,

Yokohama 236, Japan

INOUE, S., H. NAGASE, S. SATOH, M. SAITO, M. EGAWA, K. TANAKA AND Y. TAKAMURA. Role of the efferent and afferenr vagus nerve in the development of ventromedial hypothalamic (VMH) obesiry. BRAIN REF.?BULL 27(3/4) 51 l-515, 1991. -Hyperactivity of the vagus nerve and hypoactivity of the sympathetic nerves after VMH lesions both cooperatively contribute to the development of VMH obesity, mainly through h~~nsulinemia. Recently it has turned out that we should discriminate the role of the efferent vagus from that of the afferent vagus in the pancreatic hormone secretion. The hepatic branch is the main pathway of afferent fibers in the vagus, while the celiac (pancreatic) branch is tbe main pathway of efferent fibers. We investigated the role of the afferent and efferent vagus on the development of VMH obesity using the sectioning of the hepatic and celiac branch. Celiac vagotomy decreased insulin secretion and food intake, while hepatic vagotomy did not change them. The results suggested that the efferent vagus plays the main role in the development of VMH obesity, while the role of afferent vagus seems less apparent. VMH obesity

Hyperinsulinemia

Afferent vagus

Efferent vagus

obese (6). However, several investigations suggested that this interpretation may be incorrect, since it was demonstrated that VMH-ies~oned adult rats ~ifested obesity even if hy~~hagia was prevented by force feeding (12), and VMH-lesioned weanling rats remained normophagic yet became obese (8). When hyperinsulinemia was first reported in VMH obesity (lo), the hyperinsulinemia was presumed to be secondary to hyperphagia and obesity, since the hy~~nsuline~a disappeared after fasting. But restricted feeding or pair-feeding failed to eliminate hyperinsulinemia ( 11,14). This hyperinsulinemia occurs within minutes or in the first few days after ventromedial hy~~~~c lesions, even without hy~~hagia or obesity (2,14). Furthermore, it was demonstrated that when beta-cells of the pancreas were destroyed beforehand with streptozotocin to prevent the increase of insulin, obesity and hyperphagia were prevented or remarkably attenuated (9,42). Since insulin ~atment can produce hy~~hagia and obesity, the focus of attention gradually shifted to the hyperinsulinemia. However, the question remained unsettled as to whether hyperphagia or hyperinsulinemia is more important in the development of this obesity. The mechanism for the hy~~nsulinemia in VMH obesity also remained to be settled. For the mechanism of hyperinsulinemia after VMH lesions, two hypotheses had been advanced. One is humoral mediation, postulating that a “hypothalamic

it has turned out that hypothalamic obesity is produced by destruction of various sites in the hypothalamus. Ventromedial hy~~al~c obesity is produced by VMH lesions (13). Paraventricular lesions also produce obesity (24). Knife cut between the VMH and lateral hypothalamus (LH) can produce obesity (4). Monosodium glutamate treatment destroys arcuate nucleus along the with VMH and produces obesity (29). H~o~~arnic islands, produced by Halasz knife, can produce obesity (30). It has now appeared that the pathogenesis of VMH obesity is not only one, but multifactrical; hyperinsulinemia, hyperphagia, decreased energy expenditure and autonomic derangements. However, each factor is not equal for the development of VMH obesity. RECENTLY

IMPORTANCE OF NEURALLY MEDIATED HYPE~NS~~A DE~LOP~~ OF VMH OBESITY

IN THE

Brobeck found hyperphagia in VMH obesity (5). In the many years since then, hypothalamic obesity has been considered to be due to the destruction of a “satiety center” in the ventromedial hy~~~arnus. Ablation of this “satiety center” was believed to remove the inhibitory influences to a “hunger center” in the lateral hypothalamus and allow excess feeding. This intake of excessive amounts of food energy made the animals

‘Requests for reprints should be addressed to Shuji Inoue, M.D., The Third Department of Internal Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236 Japan.

511

512

JNOUE

o.-

0

7

1 Tim;

3

4

(weeks)

FIG. 1. Change of body weight after VMH lesions in rats with pancreatic transplants. 0 1977 Macmillan Magazines Ltd. Reprinted from (17) with permission. VMH-lesioned rats with intact pancreas; VMH-lesioned rats with pancreatic transplants; Sham VMH-lesioned rats with intact pancreas; Sham V~-lesioned rats with pancreatic transplants.

factor” which stimulates or suppresses pancreatic beta-cells is released into the circulatory system from the hypothalamus which directly increases insulin secretion (15,25). The second hypothesis is neural mediation, postulating that pancreatic beta-cells are stimulated though the altered tone of the autonomic nervous system (1). Experiments were carried out to test these two hypotheses as to whether hyperinsulinemia or hyperphagia is more important for the development of VMH obesity, and whether humoral or neural mediation exerts the main role for the mechanism of hy~rinsulinemia (l&19). In highly inbred Lewis rats, original pancreatic beta-cells were destroyed by trea~ent of streptozotin. Subsequently, several fetal pancreases were transplanted underneath the renal capsules. Through this manipulation, we produced rats with denervated pancreatic beta-cells. After recovery from diabetes. VMH lesions were performed. VMH-lesioned

rats with an intact pancreas gained weight rapidly after VMH lesions, averaging 120 g in 4 weeks (Fig. I). VMH-lesioned rats with pancreatic transplants gained 30 g but this increase was not significant, compared to nonlesioned control rats. VMH-lesioned rats with an intact pancreas were fatter than nonlesioned control rats when body fatness was compared by the methods of body density and Lee Index, while VMH-lesioned rats with pancreatic transplants showed no difference from controls (Table I ). Food intake of VMW-lesioned rats with an intact pancreas increased about 70%, whereas VMH-lesioned rats with pancreatic transplants increased only about 20% without hyperinsulinemia (Table 1). Serum insulin levels in VMH-fesioned rats with an intact pancreas were about 3 times higher than in nonlesioned control rats with intact pancreatic tissue, whereas VMH-lesioned rats with pancreatic transplants showed no difference from the unlesioned rats with pancreatic transplants (Table 1). The increase of food intake by 20% in VMH-lesioned rats with pancreatic transplants failed to produce obesity in four weeks. There remains a possibility that this increase can produce obesity, if we had observed for a much longer period, but it is clear that without hyperinsulinemia, the characteristic rapid weight gain of VMH obesity disappears. If a humoral factor was the stimulus to pancreatic beta-cells, this factor should have reached to the pancreatic tissue underneath the renal capsule and should have increased insulin release. Our results supported the hypotheses that hy~rinsulinemia of hy~thalamic obesity is neurally mediated, and more important in the development of VMH obesity. NEURAL COMPONENTS FOR THE HYPERINSULINEMIA IN VMH OBESITY

After VMH lesions, the vagus nerve becomes hyperactive (16, 32. 33), on the other hand, the sympathetic nervous system appears to be hypoactive after VMH lesions (20,28). Powley and Opsahl (32) first tested the importance of the autonomic nervous system in the development of VMH obesity and demonstrated that subdiaphragmatic vagotomy reversed the VMH obesity. We pursued their study and confirmed that subdiaphragmatic vagotomy reversed the VMH obesity (16). However, we also found that this was not primarily due to reversal of h~~rinsuiinemia but due to remarkable decrease in food intake secondary to disturbance of gastrointestinal function by the vagotomy under the diaphragm (16).

TABLE I EFFECTS OF VMH LESIONS ON BODY FATNESS,

Body Density”

Group

VMH Intact Pancreas

1.0253

Sham Intact Pancreas VMH Pancreatic Sham Pancreatic

i 0.0167T

ET AL.

FOOD INTAKE AND SERUM INSULIN

Lee Index”

Food lntakeb (g/day)

Serum Insulin” (ngiml)

0.327

t 0.004t

29.8 _s 0.8:

9.7 i 0.2:‘

1.0770 t 0.0030

0.288

” 0.002

17.1 + 0.4

4.1 ir 0.2

Transplants

1.0654lr 0.0116

0.296

+ 0.002

20.5 t O.S*

5.3 3 0.4

Transpl~ts

1.0794 t 0.0046

0.292

-ir 0.003

16.7 i 0.4

5.3 t 0.3

Values are means c SE. Lee Index = body wt. (g)/length (cm) r/l. “Data were obtained 4 weeks after VMH lesions. ‘Data were obtained during 2nd week. *~“0.05. QKO.01 compared to corresponding sham groups.

EFFERENT AND AFFERENT

VAGUS

513

IN VMH OBESITIES

TABLE

2

PLASMAINSULIN(nglml)AFTERIV GLUCOSE,IP GLUCOSEANDIP ARGININEIN VMH-LESIONED RATS Time (min)

0

5

10

15

30

IV glucose (0.5 g/kg) Sham Hepatic-vagotomy Celiac-vagotomy

2.15 ? 0.24 2.10 ? 0.16 1.23 ” 0.14t

8.52 2 0.69 7.57 2 0.63 4.83 2 0.40t

7.51 * 0.68 6.03 + 0.75 3.49 t 0.30t

3.68 2 0.38 3.31 + 0.24 2.44 t 0.26

2.51 ? 0.25 2.39 + 0.18 2.02 2 0.20

IP glucose (1 g/kg) Sham Hepatic-vagotomy Celiac-vagotomy

3.10 2 0.51 2.90 ? 0.47 1.60 + 0.45t

14.73 2 0.75 13.65 + 0.67 11.80 ? 0.65*

15.25 ? 0.98 13.94 2 0.78 10.82 2 0.65t

11.37 2 0.82 10.84 ? 0.70 9.15 + 0.64

5.04 ” 1.00 5.39 + 0.83 3.92 ? 0.87

IP arginine (1 gikg) Sham Hepatic-vagotomy Celiac-vagotomy

2.60 2 0.46 3.01 ‘- 0.56 1.10 * 0.37*

12.18 2 1.23 9.65 ? 1.05 9.00 ? 0.98

17.96 2 1.86 14.90 * 1.12 7.65 + 1.59t

7.65 + 0.98 8.61 + 1.13 5.39 5 0.91

2.58 + 0.55 3.15 t 0.62 2.11 t 0.36

*p