Cell proliferation in visceral organs induced by ventromedial hypothalamic (VMH) lesions: Development of electrical VMH lesions in mice and resulting pathophysiological profiles

Abstract

AnimAl models of obesity are mainly categorized as hypothalamic, genetic and diet-induced obesity [1,2]. Hypothalamic obesity was first identified by Hetherington and Ranson [3] in 1940, based on the observation that obesity was produced by electrical destruction of bilateral ventromedial hypothalamic nuclei (VMH) in rats. Subsequently, hypothalamic obesity has been thought of exclusively as obesity induced by VMH lesions. However, it is now recognized that hypothalamic obesity is also produced by the destrucCell proliferation in visceral organs induced by ventromedial hypothalamic (VMH) lesions: Development of electrical VMH lesions in mice and resulting pathophysiological profiles Abstract. We have found that ventromedial hypothalamic (VMH) lesions produced by electrocoagulation induce cell proliferation in visceral organs through vagal hyperactivity, and also stimulate regeneration of partially resected liver in rats. To facilitate identification of proliferative and/or regenerative factors at the gene level, we developed electrical production of VMH lesions in mice, for which more genetic information is available compared to rats, and examined the pathophysiological profiles in these mice. Using ddy mice, we produced VMH lesions with reference to the previously reported method in rats. We then examined the pathophysiological profiles of the VMH-lesioned mice. Electrical VMH lesions in mice were produced using the following coordinates: 1.6 mm posterior to the bregma, anteriorly; 0.5 mm lateral to the midsagittal line, transversely; and 0.2 mm above the base of the skull, vertically, with 1 mA of current intensity and 10 s duration. The VMH-lesioned mice showed similar metabolic characteristics to those of VMH-lesioned rats, including body weight gain, increased food intake, increased percentage body fat, and elevated serum insulin and leptin. However, there were some differences in short period of hyperphagia, and in normal serum lipids compared to those of VMHlesioned rats. The mice showed a similar cell proliferation in visceral organs, including stomach, small intestine, liver, and, exocrine and endocrine pancreas. In conclusion, procedures for development of VMH lesions in mice by electrocoagulation were developed and the VMH-lesioned mice showed pathophysiological profiles similar to those of VMH-lesioned rats, particularly in cell proliferation in visceral organs. These findings have not been observed previously in gold thioglucoseinduced VMH-lesioned mice. This model may be a new tool for identifying factors involved in cell proliferation or regeneration in visceral organs. [5,6], and biochemical changes including hypergastric acid secretion [7,8], hyperlipidemia [1], hyperinsulinemia [1,9], and hyperleptinemia [10,11]. Furthermore, we found cell proliferation in visceral organs (liver, stomach, small intestine, and pancreas) in these rats using [3 H] thymidine uptake [12][13][14]. We also found that cell proliferation in vis-

Vagal Hyperactivity Due to Ventromedial Hypothalamic Lesions Increases Adiponectin Production and Release

“…A transient increase in food intake in the VMHlesioned mice was observed at 1 week after the operation, as we observed in our previous study (24), but daily food intake at 4 weeks did not differ significantly between the VMH-and sham VMH-lesioned mice (Table 1). Total body fat at 1 and 4 weeks was significantly higher in VMHlesioned mice compared with sham VMH-lesioned mice, and VMH-lesioned mice had greater total body fat at 4 weeks compared with 1 week (Table 1).…”

“…Bilateral VMH lesions in mice and rats were produced by electrical destruction using a Narishige stereotaxic instrument (Tokyo, Japan) (24,25). In mice, an anodal current of 1 mA was passed for 10 s through a stainless steel needle insulated with Epoxylite, except for 1 mm at the top, for formation of bilateral electrical lesions in the VMH.…”

Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats

“…These islet modifications demonstrate that increased insulin secretion, at stimulatory glucose concentrations ( Figure 3A ), as well as hyperinsulinemia ( Table 2 and Figure 2C ), are associated with greater numbers of pancreatic β-cells in MSG islets. Several lines of experimental evidence suggest that the vagus nerve controls cellular proliferation in different tissues in ventromedial hypothalamic lesioned rats ( 4 , 7 , 27 - 29 ). This increased proliferation was inhibited by bilateral subdiaphragmatic vagotomy or by administration of the cholinergic blocker, atropine 4 , 27 .…”

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

“…Obesity is caused by dysregulation of energy metabolism, a process that is finely controlled by the central nervous system (CNS); the hypothalamus, in particular, has emerged as the master regulator of whole-body energy homeostasis ( Seoane-Collazo et al, 2015 ). Hormonal and nutrient-sensing hypothalamic nuclei coordinate central and peripheral responses to maintain normal body weight, food intake, energy expenditure, and nutrient distribution ( Valassi et al, 2008 ; Suzuki et al, 2011 ; Müller, 2017 ). In these nuclei, specialized neuronal populations are interconnected to transmit and receive information from different extrahypothalamic brain regions, coordinating whole-body energy homeostasis ( Lubaczeuski et al, 2015 ).…”