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Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters

Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration. Keywords Behavior, Endocrinology and metabolism, neurology, obesity Received 01 December 2020; accepted 11 December 2020 negative effects on the quality of life, work productivity, and Introduction healthcare costs. Diet is one of the risk factors for obesity. The modern-day Body weight is determined by an interaction between genetic, energy-dense diet may be the reason for the increasing environmental, and psychosocial factors. Physiologic prevalence of obesity. Li et al. have documented that a diet- studies had previously suggested that weight and energy induced animal model is the apt model to study obesity in the stores are homeostatically regulated, with either weight loss or weight gain producing concerted changes in energy intake and expenditure that resist the obesity initial perturbation. Department of Physiology, All India Institute of Medical Sciences (AIIMS) Obesity is because of excessive fat accumulation that may Jodhpur, Jodhpur, Rajasthan, India impair health. It adversely affects nearly all physiological Department of Physiology, Jawaharlal Institute of Postgraduate Medical functions of the body and poses a significant public health Education and Research (JIPMER), Puducherry, Pondicherry, India threat. It increases the risk for developing multiple disease Corresponding author: 3, 4 conditions, such as diabetes mellitus, cardiovascular Archana Gaur T, Department of Physiology, AIIMS Jodhpur, Jodhpur, 4, 5 6 disease, several types of cancers, musculoskeletal Rajasthan342005, India. 7 8 E-mail: drarchana85@gmail.com disorders, and poor mental health, all of which have Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences general population. Various diet models have been studied so under mild anesthesia (ether). A quantification of the thyroid 10, 11 far. Studies have shown a significant difference in glucose hormone profile—plasmathyroid stimulating hormone[TSH; intolerance between high-carbohydrate-diet-induced obesity Human TSH chemiluminescencekit, Siemens, USA and high-fat-diet-induced obesity. Our Indian diet is rich in (110732)], total triiodothyronine[T ;Human TT3 RIA kit, carbohydrates, and hence we chose to study the high-sucrose- Immunotech, Czech(119780)], and total thyroxine[T ;Human induced obesity. TT4 RIA kit, Immunotech, Czech (06490092)]—and the lipid Ventromedial hypothalamus (VMH) is designated as the profile (chemiluminescence, Siemens, USA)was carried out principal satiety center governing feeding behavior. VMH is using the isolated serum as per the manufacturer’s guidelines. linked to the regulation of food intake and body weight in Blood glucose was measured using the glucose oxidase and animals as well as humans. A lesion of VMH is found to peroxidase method. Insulin concentration was measured cause obesity. Although there are many studies on using the enzyme-linked immunosorbentassay kit (Millipore, hypothalamic obesity (created by an ablation of VMH) and USA). Insulin resistance was calculated using the standard diet-induced obesity, there is very less data available till date formulae for the homeostatic model assessment of insulin about the role of VMH in sucrose-induced obesity on resistance (HOMA-IR). For post-lesion values, 5 mL of rat metabolic parameters such as insulin, thyroid profile, lipid blood was collected under anesthesia by cardiac puncture profile, and glucose. Hence, the present study was conceived. before sacrificing. We administered two-fold increased amount of ketamine intraperitoneally before sacrificing the animal. Methods This is an experimental animal study done in the Department Lesion of Physiology, Jawaharlal Institute of Postgraduate Medical A lesion of the VMH was made according to the coordinates Education and Research, Puducherry. We commenced the provided from the stereotaxic atlas for rat brain by König and study after obtaining the approval from both the institute Klippelin 1974. scientific advisory committee and animal ethics committee. In the experimental rats, the electrodes were passed The guidelines of the Committee for the Purpose of Control bilaterally and a mild shock was given for an electrolytic and Supervision of Experiments on Animals were diligently ablation of the VMH nucleus. In the control rats, a sham followed in the study. A total of 24 (12 males and 12 females) lesion was made by placing electrodes near the VMH, but institute-bred healthy adult albino rats of Wistar strain without shock to undergo the same level of stress as the weighing between 150 and 250 g were used for the study. The experimental rats. After the lesion, the rats were accommodated rats were housed in individual plastic cages with wire lids. A to their cages with standard rodent chow and water for a layer of husk was spread on the floor of the cages. A 12-h fortnight, and we monitored them for bleeding and distress light–dark cycle was maintained. They were fed on standard till their recovery. We recorded the post-lesion variables rat chow and allowed to habituate for 10 days. ensuring the complete recovery of the rats from the surgical After a habituation period of 10 days, the rats were fed on procedure. standard rodent chow supplemented with a 32% sucrose solution and normal tap water. Diet and water were provided adlibitum for a period of 10 weeks to produce the sucrose- Statistical Analysis induced obese model of rats. Once obesity was attained, they were shifted to standard rodent chow. After 10 days of All the data were analyzed and expressed in mean ± SD. habituation, 40 g of standard rodent chow and 100 mL of Unpaired t-test was done between the groups and paired fresh tap water were provided ad libitum every day. Daily t-test was done before and after the lesion. All the data food intake and body weight were measured for one week to analysis was carried out in the IBM SPSS statistics software determine the mean 24-h basal recordings, and pre-lesion (version 20, New York, USA). The significance was set atthe blood was collected. The rats were divided randomly into two P-value <.05. groups: one serving as the control group and the other as the experimental group. The sample size in each group was 12 (6 Results males and 6 females). In the experimental group, a lesion was made bilaterally in the VMH nucleus, and the control group Food intake was higher in the experimental rats before the included weight- and gender-matched rats, for which sham lesion, and the increase in food intake was significantly lesions were made. higher after the lesion when compared with the controls as Nucleus Anterior Lateral Coordi- Vertical Coordi- Blood Collection Coordinates nates nates Blood samples were collected after seven days of baseline VMH 0.45 mm ±0.05mm 0.82 mm recordings from the jugular vein for a biochemical analysis Gaur et al. 3 S tudy D esign 24 Adult rats (3 months old) (10 days habituation) Sucrose -supplemented diet (10 weeks) Obese model (10 days habituation to a standard diet) Basal parameters {body weight, food intake, biochemical parameters (averaged over one wee k)} VMH lesion/ Sham lesion (Two w eeks) Recovery (Four w eeks) Post -lesion parameters {body weight, food intake, biochemical parameters (averaged over four weeks)} Sacrifice Figure 1. Study Design 24 Adult rats (3 months old) well as with their pre-lesion values. Body weight was group after the lesion in comparison to the control group, but comparable between the control and experimental rats both only blood glucose and HOMA-IR were statistically before and after the lesion (Table 1). significant. The HOMA-IR value of controls was also Males showed that pre-lesion values were comparable significant after the lesion (Table 4). among the groups. All the values were increased in both the control and There wasa significant increase in both food intake and experimental groups. Significant differences were observed body weight compared to controls as well as to the pre-lesion in total cholesterol (TC), triglycerides (TG), and low-density values, except for the food intake in comparison to controls lipoprotein (LDL), excepthigh-density lipoprotein(HDL) and which was not statistically significant(Table 2). very-low-density lipoprotein (VLDL;Table 5). Blood glucose, insulin, and HOMA-IR were increased in In males, all the values were increased after the lesion in the experimental group after the lesion in comparison to the both the control and experimental groups, but there was a control group, but only blood glucose and HOMA-IR were significant increase in TC and LDL values compared to their statistically significant (Table 3). pre-lesion values. The TG value of controls also increased The males also showed similar results as blood glucose, significantly(Table 6). insulin, and HOMA-IR were increased in the experimental 4 Annals of Neurosciences Table 1. Comparison of Body Weight and Food Intake in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Food intake (g) Pre-lesion 09.09 ± 1.309 11.025 ± 1.856 .0635 Post-lesion 10.94 ± 1.281 15.45 ± 2.469 .0026 Pre vs.post (P-value) 0.0329 0.0056 Bodyweight (g) Pre-lesion 183.16 ± 15.105 190.66 ± 15.718 .4191 Post-lesion 190.66 ± 12.972 197.83 ± 12.844 .3587 Pre vs.post (P-value) 0.3779 0.4072 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 2. Comparison of Body Weight and Food Intake in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Food intake (g) Pre-lesion 16.07 ± 1.385 15.15 ± 1.953 .3688 Post-lesion 16.66 ± 2.965 19.16 ± 1.396 .0912 Pre vs.post (P-value) 0.6682 0.0022 Bodyweight (g) Pre-lesion 266.66 ± 20.726 268.0 ± 20.914 .9134 Post-lesion 286.50 ± 17.593 329.66 ± 20.862 .0031 Pre vs.post (P-value) 0.1041 0.0005 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 3 .Comparison of Blood Glucose, Insulin, and HOMA-IR in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Blood glucose (mg/dL) Pre-lesion 72.83 ± 8.519 74.0 ± 9.711 .8289 Post-lesion 79.33 ± 12.111 114.5 ± 16.566 .0018 Pre vs.post (P-value) 0.3075 0.0004 Insulin (ng/mL) Pre-lesion 0.504 ± 0.216 1.237 ± 0.503 .0083 Post-lesion 1.60 ± 0.768 1.98 ± 0.703 .3923 Pre vs.post (P-value) 0.0072 0.0615 HOMA-IR Pre-lesion 3.93 ± 1.10 5.420 ± 1.129 .0431 Post-lesion 7.156 ± 2.382 13.424 ± 3.041 .0026 Pre vs.post (P-value) 0.0131 0.0001 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 4. Comparison of Blood Glucose, Insulin, and HOMA-IR in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Bloodglucose (mg/dL) Pre-lesion 92.33 ± 6.218 91.0 ± 8.931 .7708 Post-lesion 102.83 ± 15.864 132.83 ± 19.670 .0156 Pre vs.post (P-value) 0.1621 0.0008 Insulin (ng/mL) Pre-lesion 2.349 ± 1.101 1.736 ± 1.436 .4260 Post-lesion 2.36 ± 1.332 3.526 ± 1.627 .2042 Pre vs.post (P-value) 0.9879 0.0709 HOMA-IR Pre-lesion 12.842 ± 1.101 9.354 ± 1.291 .0005 Post-lesion 14.369 ± 1.230 27.732 ± 4.670 ˂.0001 Pre vs.post (P-value) 0.0469 ˂0.0001 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Gaur et al. 5 Table 5. Comparison of the Lipid Profile in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TC (mg/dL) Pre-lesion 42.33 ± 4.803 41.0 ± 6.00 .6806 Post-lesion 67.5 ± 6.950 61.5 ± 9.586 .2428 Pre vs.post (P-value) ˂0.0001 0.0013 TG (mg/dL) Pre-lesion 109.16 ± 10.607 117.0 ± 8.99 .1973 Post-lesion 141.33 ± 17.340 157.83 ± 10.362 .0733 Pre vs.post (P-value) 0.0031 ˂0.0001 HDL (mg/dL) Pre-lesion 27.16 ± 4.167 28.66 ± 5.203 .5936 Post-lesion 30.33 ± 4.131 32.5 ± 4.231 .3898 Pre vs.post (P-value) 0.2152 0.1910 LDL (mg/dL) Pre-lesion 5.96 ± 1.228 5.06 ± 2.061 .3798 Post-lesion 25.9 ± 7.817 28.33 ± 7.581 .5966 Pre vs.post (P-value) 0.0001 ˂0.0001 VLDL (mg/dL) Pre-lesion 14.83 ± 2.121 13.4 ± 1.780 .2345 Post-lesion 16.26 ± 3.468 14.56 ± 2.072 .3269 Pre vs.post (P-value) 0.4091 0.3227 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Table 6. Comparison of the Lipid Profile in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TC (mg/dL) Pre-lesion 47.83 ± 7.083 45.5 ± 6.775 .5733 Post-lesion 121.16 ± 11.631 122.33 ± 11.753 .8659 Pre vs.post (P-value) ˂0.0001 ˂0.0001 TG (mg/dL) Pre-lesion 66.83 ± 6.242 72.33 ± 7.952 .2122 Post-lesion 82.0 ± 12.979 82.33 ± 14.855 .9681 Pre vs.post (P-value) 0.0274 0.1767 HDL (mg/dL) Pre-lesion 18.5 ± 2.074 20.5 ± 3.937 .2967 Post-lesion 22.66 ± 6.154 21.5 ± 3.271 .6921 Pre vs.post (P-value) 0.1477 0.6425 LDL (mg/dL) Pre-lesion 13.3 ± 4.193 10.53 ± 2.500 .1947 Post-lesion 74.1 ± 11.093 74.28 ± 8.957 .9759 Pre vs.post (P-value) ˂0.0001 ˂0.0001 VLDL (mg/dL) Pre-lesion 23.383 ± 3.250 24.6 ± 3.590 .5519 Post-lesion 26.4 ± 5.96 25.56 ± 4.971 .7963 Pre vs.post (P-value) 0.3019 0.7094 Notes:Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. 6 Annals of Neurosciences Table 7. Comparison of Thyroid Profile in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TSH (µIU/mL) Pre-lesion 0.33 ± 0.182 0.226 ± 0.141 .2944 Post-lesion 0.44 ± 0.283 0.395 ± 0.177 .7480 Pre vs.post (P-value) 0.4419 0.0973 T (ng/dL) Pre-lesion 0.93 ± 0.902 0.985 ± 0.168 .9216 Post-lesion 0.999 ± 0.986 0.642 ± 0.083 .3976 Pre vs.post (P-value) 0.9019 0.4152 T (µg/dL) Pre-lesion 3.167 ± 2.982 1.815 ± 0.77 .3075 Post-lesion 3.09 ± 1.784 3.56 ± 1.058 .5911 Pre vs.post (P-value) 0.9578 0.0085 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TSH, thyroid stimulating hormone; T , Tri-iodothyronine; T , Thyroxine. 3 4 Table 8. Comparison of Thyroid Profile in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TSH (µIU/mL) Pre-lesion 0.615 ± 0.439 0.608 ± 0.405 .9777 Post-lesion 0.84 ± 0.714 0.63 ± 0.197 .5032 Pre vs.post (P-value) 0.5257 0.9071 T (ng/dL) Pre-lesion 0.832 ± 0.68 0.658 ± 0.084 .5478 Post-lesion 0.35 ± 0.246 0.30 ± 0.193 .7035 Pre vs.post (P-value) 0.1336 0.0019 T (µg/dL) Pre-lesion 2.017 ± 1.213 2.136 ± 0.475 .8274 Post-lesion 4.32 ± 3.585 2.59 ± 1.553 .3035 Pre vs.post (P-value) 0.1669 0.5091 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion.Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TSH, thyroid stimulating hormone; T , Tri-iodothyronine; T , Thyroxine. 3 4 T4 significantly increased in the experimental group after nucleus. We observed a varied difference in male and female the lesion (Table 7). rats. The female rats showed an increase in food intake after T3 significantly decreased in the experimental group the lesion in comparison to the control rats. But this did not result in a weight gain in them. However, in male rats, there (Tables 7 and 8). was a significant weight gain along with hyperphagia. This is in confirmation with our previous study by Dev et al., where Discussion there was an increase in body weight in both male and female rats compared to their own control rats following the VMH VMH is designated as the principal satiety center governing lesion; the increase was significant in male rats and not feeding behavior. Established pathways involving orexigenic significant in female rats. Hence, the females are protected neuropeptide Y and agouti-related polypeptide, as well as the from hyperphagic obesity to some extent in comparison to anorexigenic pro-opiomelanocortin and cocaine- and males. This indicates a dissociation of the mechanism amphetamine-regulated transcript neurons project from the controlled by VMH regulation in different genders. On the arcuate nucleus to other important hypothalamic nuclei, contrary, Coxet al. observed that extensive bilateral VMH including the paraventricularnucleus, dorsomedial nucleus, damage resulted in a diminished rate of weight gain inspite of VMH, and lateral hypothalamus nuclei. Apart from these, an increased food intake in both the genders. They compared there are also projections to and from other brain stem areas, the rate of weight gain instead of the overall weight gain, cortical areas, and reward pathways. which was not assessed in our study. Another study by This study was conducted to assess the role of VMH in Sclafani et al. showed that vagotomy suppresses hyperphagia in rats on a chow diet and sucrose solution when VMH was already-obese rats. The rats were made obese by providing a damaged, but not on a palatable mixed diet. This suggests sucrose solution, and then a lesion was made in the VMH Gaur et al. 7 that VMH is not involved in the regulation of feeding when a localized in the brain and pituitarygland. Previous studies palatable diet is given. Hence, VMH is not the final common have found that T3 has a direct influence on feeding; T3 pathway for the regulation of feeding. directly injected into the ventromedial nucleus increased the The important parameters of energy homeostasis are blood food intake by four times and the inhibition of thyroid glucose and insulin levels. The blood glucose levels hormone receptors in VMH reverses the weight loss observed significantly increased after the lesion in both males and 26 in hyperthyroidism, interpreting that the thyroid hormone females, and a corresponding increase in insulin levels also regulates the food intake and body weight via VMH through observed in both the groups, though statistically not the hypothalamus–pituitary–thyroid axis. However, at this significant. But the HOMA-IR values were quite significant stage, we are not clear whether the VMH lesion resulted in a in both males and females. The control rats also had a deficiency of type II deiodinase or there was a decreased significant increase in insulin which may be, to maintain expression of receptors, which needs further evaluation. homeostasis for the increase in blood glucose, an effect of the This study was done only with biochemical parameters; sucrose diet. Therefore, the sucrose diet by itself can cause a this is a major limitation of the study. Other parameters like diabetes-like condition where there is an increase in blood fat % and other metabolic and inflammatory changes were glucose, insulin, and insulin resistance, and the VMH lesion not measured. A future study with fat % and other metabolic further exaggerates this. In a study by Cao et al. the and inflammatory changes associated with obesity could be abdominally obese and normal-weight rats, which were planned. Since aVMH lesion exaggerates obesity, the role of created by giving a modified sucrose diet, showed a drugs and stem cell therapy, which enhance the neurological significantly reduced glucose-to-insulin ratio, demonstrating recovery, may be explored in the treatment of obesity. a decreased overall capability of disposing of ectogenic glucose. Another study by Yang et al. described that a sucrose-rich diet can cause a change in insulin, signaling by Conclusion the downregulation of genes involved in the insulin secretion. A sucrose diet produces obesity, which is similar to the There was a significant change in post-lesion values of TC, metabolic syndrome with insulin resistance and dyslipidemia, TG, and LDL and an insignificant rise in HDL and VLDL in and aVMH lesion further exaggerates it. Males are more both the control and experimental groups in females. Males prone to this exaggeration. Females seem to be protected to also showed similar results, except for TG which was higher some extent which may be because of the effect estrogen, in females. This suggests that the VMH lesion did not produce which needs further analysis. these effects, but may be because of a sucrose diet there are higher values in both the control and experimental groups. Acknowledgment This is in confirmation with a study by Yang et al., where the We thank JIPMER for providing the intramural research grant for measurement of hepatic TG clearly indicated an increased this study. hepatic lipid accumulation in response to the high-fat and high-sucrose diet as early as two weeks. This may be explained Author Contribution by the upregulation of genes involved in lipid metabolism and inflammation. The high triglyceridemia in the high-sucrose All authors have equally contributed. diet was because of an increased hepatic triacylglycerol secretion and a decreased removal of triacylglycerol from the Ethical Statement plasma in contrast to the high-fat-diet-induced triglyceridemia, Ethical clearance wasobtained before the start of experiment and all which is because of a decreased removal of triacylglycerol 23 procedures followed the CPCSEA guidelines. alone. Another study by Cao et al. observed that a modified high-sucrose diet produces hepatic lipidosis and hepatocyte 21 Declaration of Conflicting Interests mitochondrial swelling. To infer that sucrose diet creates a model of dyslipidemia. The authors declared no potential conflicts of interest with respect to Thyroid hormone is a major regulator of energy metabolism the research, authorship, and/or publication of this article. and food intake, greatly influencing the energy homeostasis of the body. In our study, the experimental group of females Funding showed a significant rise in T4 values, whereasthe experimental The conduct of this project was funded by the JIPMER intramural group of males showed a decrease in T3 values.The increasedT4 research fund. and decreased T3values in the experimental group of both the genders after lesion, may be because of the reduced conversion ORICD iD of T4 to T3. 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Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters

Annals of Neurosciences , Volume OnlineFirst: 1 – Jan 1, 2021

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Abstract

Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration. Keywords Behavior, Endocrinology and metabolism, neurology, obesity Received 01 December 2020; accepted 11 December 2020 negative effects on the quality of life, work productivity, and Introduction healthcare costs. Diet is one of the risk factors for obesity. The modern-day Body weight is determined by an interaction between genetic, energy-dense diet may be the reason for the increasing environmental, and psychosocial factors. Physiologic prevalence of obesity. Li et al. have documented that a diet- studies had previously suggested that weight and energy induced animal model is the apt model to study obesity in the stores are homeostatically regulated, with either weight loss or weight gain producing concerted changes in energy intake and expenditure that resist the obesity initial perturbation. Department of Physiology, All India Institute of Medical Sciences (AIIMS) Obesity is because of excessive fat accumulation that may Jodhpur, Jodhpur, Rajasthan, India impair health. It adversely affects nearly all physiological Department of Physiology, Jawaharlal Institute of Postgraduate Medical functions of the body and poses a significant public health Education and Research (JIPMER), Puducherry, Pondicherry, India threat. It increases the risk for developing multiple disease Corresponding author: 3, 4 conditions, such as diabetes mellitus, cardiovascular Archana Gaur T, Department of Physiology, AIIMS Jodhpur, Jodhpur, 4, 5 6 disease, several types of cancers, musculoskeletal Rajasthan342005, India. 7 8 E-mail: drarchana85@gmail.com disorders, and poor mental health, all of which have Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences general population. Various diet models have been studied so under mild anesthesia (ether). A quantification of the thyroid 10, 11 far. Studies have shown a significant difference in glucose hormone profile—plasmathyroid stimulating hormone[TSH; intolerance between high-carbohydrate-diet-induced obesity Human TSH chemiluminescencekit, Siemens, USA and high-fat-diet-induced obesity. Our Indian diet is rich in (110732)], total triiodothyronine[T ;Human TT3 RIA kit, carbohydrates, and hence we chose to study the high-sucrose- Immunotech, Czech(119780)], and total thyroxine[T ;Human induced obesity. TT4 RIA kit, Immunotech, Czech (06490092)]—and the lipid Ventromedial hypothalamus (VMH) is designated as the profile (chemiluminescence, Siemens, USA)was carried out principal satiety center governing feeding behavior. VMH is using the isolated serum as per the manufacturer’s guidelines. linked to the regulation of food intake and body weight in Blood glucose was measured using the glucose oxidase and animals as well as humans. A lesion of VMH is found to peroxidase method. Insulin concentration was measured cause obesity. Although there are many studies on using the enzyme-linked immunosorbentassay kit (Millipore, hypothalamic obesity (created by an ablation of VMH) and USA). Insulin resistance was calculated using the standard diet-induced obesity, there is very less data available till date formulae for the homeostatic model assessment of insulin about the role of VMH in sucrose-induced obesity on resistance (HOMA-IR). For post-lesion values, 5 mL of rat metabolic parameters such as insulin, thyroid profile, lipid blood was collected under anesthesia by cardiac puncture profile, and glucose. Hence, the present study was conceived. before sacrificing. We administered two-fold increased amount of ketamine intraperitoneally before sacrificing the animal. Methods This is an experimental animal study done in the Department Lesion of Physiology, Jawaharlal Institute of Postgraduate Medical A lesion of the VMH was made according to the coordinates Education and Research, Puducherry. We commenced the provided from the stereotaxic atlas for rat brain by König and study after obtaining the approval from both the institute Klippelin 1974. scientific advisory committee and animal ethics committee. In the experimental rats, the electrodes were passed The guidelines of the Committee for the Purpose of Control bilaterally and a mild shock was given for an electrolytic and Supervision of Experiments on Animals were diligently ablation of the VMH nucleus. In the control rats, a sham followed in the study. A total of 24 (12 males and 12 females) lesion was made by placing electrodes near the VMH, but institute-bred healthy adult albino rats of Wistar strain without shock to undergo the same level of stress as the weighing between 150 and 250 g were used for the study. The experimental rats. After the lesion, the rats were accommodated rats were housed in individual plastic cages with wire lids. A to their cages with standard rodent chow and water for a layer of husk was spread on the floor of the cages. A 12-h fortnight, and we monitored them for bleeding and distress light–dark cycle was maintained. They were fed on standard till their recovery. We recorded the post-lesion variables rat chow and allowed to habituate for 10 days. ensuring the complete recovery of the rats from the surgical After a habituation period of 10 days, the rats were fed on procedure. standard rodent chow supplemented with a 32% sucrose solution and normal tap water. Diet and water were provided adlibitum for a period of 10 weeks to produce the sucrose- Statistical Analysis induced obese model of rats. Once obesity was attained, they were shifted to standard rodent chow. After 10 days of All the data were analyzed and expressed in mean ± SD. habituation, 40 g of standard rodent chow and 100 mL of Unpaired t-test was done between the groups and paired fresh tap water were provided ad libitum every day. Daily t-test was done before and after the lesion. All the data food intake and body weight were measured for one week to analysis was carried out in the IBM SPSS statistics software determine the mean 24-h basal recordings, and pre-lesion (version 20, New York, USA). The significance was set atthe blood was collected. The rats were divided randomly into two P-value <.05. groups: one serving as the control group and the other as the experimental group. The sample size in each group was 12 (6 Results males and 6 females). In the experimental group, a lesion was made bilaterally in the VMH nucleus, and the control group Food intake was higher in the experimental rats before the included weight- and gender-matched rats, for which sham lesion, and the increase in food intake was significantly lesions were made. higher after the lesion when compared with the controls as Nucleus Anterior Lateral Coordi- Vertical Coordi- Blood Collection Coordinates nates nates Blood samples were collected after seven days of baseline VMH 0.45 mm ±0.05mm 0.82 mm recordings from the jugular vein for a biochemical analysis Gaur et al. 3 S tudy D esign 24 Adult rats (3 months old) (10 days habituation) Sucrose -supplemented diet (10 weeks) Obese model (10 days habituation to a standard diet) Basal parameters {body weight, food intake, biochemical parameters (averaged over one wee k)} VMH lesion/ Sham lesion (Two w eeks) Recovery (Four w eeks) Post -lesion parameters {body weight, food intake, biochemical parameters (averaged over four weeks)} Sacrifice Figure 1. Study Design 24 Adult rats (3 months old) well as with their pre-lesion values. Body weight was group after the lesion in comparison to the control group, but comparable between the control and experimental rats both only blood glucose and HOMA-IR were statistically before and after the lesion (Table 1). significant. The HOMA-IR value of controls was also Males showed that pre-lesion values were comparable significant after the lesion (Table 4). among the groups. All the values were increased in both the control and There wasa significant increase in both food intake and experimental groups. Significant differences were observed body weight compared to controls as well as to the pre-lesion in total cholesterol (TC), triglycerides (TG), and low-density values, except for the food intake in comparison to controls lipoprotein (LDL), excepthigh-density lipoprotein(HDL) and which was not statistically significant(Table 2). very-low-density lipoprotein (VLDL;Table 5). Blood glucose, insulin, and HOMA-IR were increased in In males, all the values were increased after the lesion in the experimental group after the lesion in comparison to the both the control and experimental groups, but there was a control group, but only blood glucose and HOMA-IR were significant increase in TC and LDL values compared to their statistically significant (Table 3). pre-lesion values. The TG value of controls also increased The males also showed similar results as blood glucose, significantly(Table 6). insulin, and HOMA-IR were increased in the experimental 4 Annals of Neurosciences Table 1. Comparison of Body Weight and Food Intake in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Food intake (g) Pre-lesion 09.09 ± 1.309 11.025 ± 1.856 .0635 Post-lesion 10.94 ± 1.281 15.45 ± 2.469 .0026 Pre vs.post (P-value) 0.0329 0.0056 Bodyweight (g) Pre-lesion 183.16 ± 15.105 190.66 ± 15.718 .4191 Post-lesion 190.66 ± 12.972 197.83 ± 12.844 .3587 Pre vs.post (P-value) 0.3779 0.4072 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 2. Comparison of Body Weight and Food Intake in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Food intake (g) Pre-lesion 16.07 ± 1.385 15.15 ± 1.953 .3688 Post-lesion 16.66 ± 2.965 19.16 ± 1.396 .0912 Pre vs.post (P-value) 0.6682 0.0022 Bodyweight (g) Pre-lesion 266.66 ± 20.726 268.0 ± 20.914 .9134 Post-lesion 286.50 ± 17.593 329.66 ± 20.862 .0031 Pre vs.post (P-value) 0.1041 0.0005 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 3 .Comparison of Blood Glucose, Insulin, and HOMA-IR in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Blood glucose (mg/dL) Pre-lesion 72.83 ± 8.519 74.0 ± 9.711 .8289 Post-lesion 79.33 ± 12.111 114.5 ± 16.566 .0018 Pre vs.post (P-value) 0.3075 0.0004 Insulin (ng/mL) Pre-lesion 0.504 ± 0.216 1.237 ± 0.503 .0083 Post-lesion 1.60 ± 0.768 1.98 ± 0.703 .3923 Pre vs.post (P-value) 0.0072 0.0615 HOMA-IR Pre-lesion 3.93 ± 1.10 5.420 ± 1.129 .0431 Post-lesion 7.156 ± 2.382 13.424 ± 3.041 .0026 Pre vs.post (P-value) 0.0131 0.0001 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Table 4. Comparison of Blood Glucose, Insulin, and HOMA-IR in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value Bloodglucose (mg/dL) Pre-lesion 92.33 ± 6.218 91.0 ± 8.931 .7708 Post-lesion 102.83 ± 15.864 132.83 ± 19.670 .0156 Pre vs.post (P-value) 0.1621 0.0008 Insulin (ng/mL) Pre-lesion 2.349 ± 1.101 1.736 ± 1.436 .4260 Post-lesion 2.36 ± 1.332 3.526 ± 1.627 .2042 Pre vs.post (P-value) 0.9879 0.0709 HOMA-IR Pre-lesion 12.842 ± 1.101 9.354 ± 1.291 .0005 Post-lesion 14.369 ± 1.230 27.732 ± 4.670 ˂.0001 Pre vs.post (P-value) 0.0469 ˂0.0001 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Gaur et al. 5 Table 5. Comparison of the Lipid Profile in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TC (mg/dL) Pre-lesion 42.33 ± 4.803 41.0 ± 6.00 .6806 Post-lesion 67.5 ± 6.950 61.5 ± 9.586 .2428 Pre vs.post (P-value) ˂0.0001 0.0013 TG (mg/dL) Pre-lesion 109.16 ± 10.607 117.0 ± 8.99 .1973 Post-lesion 141.33 ± 17.340 157.83 ± 10.362 .0733 Pre vs.post (P-value) 0.0031 ˂0.0001 HDL (mg/dL) Pre-lesion 27.16 ± 4.167 28.66 ± 5.203 .5936 Post-lesion 30.33 ± 4.131 32.5 ± 4.231 .3898 Pre vs.post (P-value) 0.2152 0.1910 LDL (mg/dL) Pre-lesion 5.96 ± 1.228 5.06 ± 2.061 .3798 Post-lesion 25.9 ± 7.817 28.33 ± 7.581 .5966 Pre vs.post (P-value) 0.0001 ˂0.0001 VLDL (mg/dL) Pre-lesion 14.83 ± 2.121 13.4 ± 1.780 .2345 Post-lesion 16.26 ± 3.468 14.56 ± 2.072 .3269 Pre vs.post (P-value) 0.4091 0.3227 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Table 6. Comparison of the Lipid Profile in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TC (mg/dL) Pre-lesion 47.83 ± 7.083 45.5 ± 6.775 .5733 Post-lesion 121.16 ± 11.631 122.33 ± 11.753 .8659 Pre vs.post (P-value) ˂0.0001 ˂0.0001 TG (mg/dL) Pre-lesion 66.83 ± 6.242 72.33 ± 7.952 .2122 Post-lesion 82.0 ± 12.979 82.33 ± 14.855 .9681 Pre vs.post (P-value) 0.0274 0.1767 HDL (mg/dL) Pre-lesion 18.5 ± 2.074 20.5 ± 3.937 .2967 Post-lesion 22.66 ± 6.154 21.5 ± 3.271 .6921 Pre vs.post (P-value) 0.1477 0.6425 LDL (mg/dL) Pre-lesion 13.3 ± 4.193 10.53 ± 2.500 .1947 Post-lesion 74.1 ± 11.093 74.28 ± 8.957 .9759 Pre vs.post (P-value) ˂0.0001 ˂0.0001 VLDL (mg/dL) Pre-lesion 23.383 ± 3.250 24.6 ± 3.590 .5519 Post-lesion 26.4 ± 5.96 25.56 ± 4.971 .7963 Pre vs.post (P-value) 0.3019 0.7094 Notes:Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. 6 Annals of Neurosciences Table 7. Comparison of Thyroid Profile in Female Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TSH (µIU/mL) Pre-lesion 0.33 ± 0.182 0.226 ± 0.141 .2944 Post-lesion 0.44 ± 0.283 0.395 ± 0.177 .7480 Pre vs.post (P-value) 0.4419 0.0973 T (ng/dL) Pre-lesion 0.93 ± 0.902 0.985 ± 0.168 .9216 Post-lesion 0.999 ± 0.986 0.642 ± 0.083 .3976 Pre vs.post (P-value) 0.9019 0.4152 T (µg/dL) Pre-lesion 3.167 ± 2.982 1.815 ± 0.77 .3075 Post-lesion 3.09 ± 1.784 3.56 ± 1.058 .5911 Pre vs.post (P-value) 0.9578 0.0085 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion. Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TSH, thyroid stimulating hormone; T , Tri-iodothyronine; T , Thyroxine. 3 4 Table 8. Comparison of Thyroid Profile in Male Rats Experimental RatsMean Parameter Control RatsMean ± SD ± SD P-Value TSH (µIU/mL) Pre-lesion 0.615 ± 0.439 0.608 ± 0.405 .9777 Post-lesion 0.84 ± 0.714 0.63 ± 0.197 .5032 Pre vs.post (P-value) 0.5257 0.9071 T (ng/dL) Pre-lesion 0.832 ± 0.68 0.658 ± 0.084 .5478 Post-lesion 0.35 ± 0.246 0.30 ± 0.193 .7035 Pre vs.post (P-value) 0.1336 0.0019 T (µg/dL) Pre-lesion 2.017 ± 1.213 2.136 ± 0.475 .8274 Post-lesion 4.32 ± 3.585 2.59 ± 1.553 .3035 Pre vs.post (P-value) 0.1669 0.5091 Notes: Control rats, rats with sham lesion; experimental rats, rats with VMH lesion.Comparison between the control and experimental groups was done using unpaired Student’s t-test. Comparison of data before and after lesion is done using paired Student’s t-test. Abbreviations: TSH, thyroid stimulating hormone; T , Tri-iodothyronine; T , Thyroxine. 3 4 T4 significantly increased in the experimental group after nucleus. We observed a varied difference in male and female the lesion (Table 7). rats. The female rats showed an increase in food intake after T3 significantly decreased in the experimental group the lesion in comparison to the control rats. But this did not result in a weight gain in them. However, in male rats, there (Tables 7 and 8). was a significant weight gain along with hyperphagia. This is in confirmation with our previous study by Dev et al., where Discussion there was an increase in body weight in both male and female rats compared to their own control rats following the VMH VMH is designated as the principal satiety center governing lesion; the increase was significant in male rats and not feeding behavior. Established pathways involving orexigenic significant in female rats. Hence, the females are protected neuropeptide Y and agouti-related polypeptide, as well as the from hyperphagic obesity to some extent in comparison to anorexigenic pro-opiomelanocortin and cocaine- and males. This indicates a dissociation of the mechanism amphetamine-regulated transcript neurons project from the controlled by VMH regulation in different genders. On the arcuate nucleus to other important hypothalamic nuclei, contrary, Coxet al. observed that extensive bilateral VMH including the paraventricularnucleus, dorsomedial nucleus, damage resulted in a diminished rate of weight gain inspite of VMH, and lateral hypothalamus nuclei. Apart from these, an increased food intake in both the genders. They compared there are also projections to and from other brain stem areas, the rate of weight gain instead of the overall weight gain, cortical areas, and reward pathways. which was not assessed in our study. Another study by This study was conducted to assess the role of VMH in Sclafani et al. showed that vagotomy suppresses hyperphagia in rats on a chow diet and sucrose solution when VMH was already-obese rats. The rats were made obese by providing a damaged, but not on a palatable mixed diet. This suggests sucrose solution, and then a lesion was made in the VMH Gaur et al. 7 that VMH is not involved in the regulation of feeding when a localized in the brain and pituitarygland. Previous studies palatable diet is given. Hence, VMH is not the final common have found that T3 has a direct influence on feeding; T3 pathway for the regulation of feeding. directly injected into the ventromedial nucleus increased the The important parameters of energy homeostasis are blood food intake by four times and the inhibition of thyroid glucose and insulin levels. The blood glucose levels hormone receptors in VMH reverses the weight loss observed significantly increased after the lesion in both males and 26 in hyperthyroidism, interpreting that the thyroid hormone females, and a corresponding increase in insulin levels also regulates the food intake and body weight via VMH through observed in both the groups, though statistically not the hypothalamus–pituitary–thyroid axis. However, at this significant. But the HOMA-IR values were quite significant stage, we are not clear whether the VMH lesion resulted in a in both males and females. The control rats also had a deficiency of type II deiodinase or there was a decreased significant increase in insulin which may be, to maintain expression of receptors, which needs further evaluation. homeostasis for the increase in blood glucose, an effect of the This study was done only with biochemical parameters; sucrose diet. Therefore, the sucrose diet by itself can cause a this is a major limitation of the study. Other parameters like diabetes-like condition where there is an increase in blood fat % and other metabolic and inflammatory changes were glucose, insulin, and insulin resistance, and the VMH lesion not measured. A future study with fat % and other metabolic further exaggerates this. In a study by Cao et al. the and inflammatory changes associated with obesity could be abdominally obese and normal-weight rats, which were planned. Since aVMH lesion exaggerates obesity, the role of created by giving a modified sucrose diet, showed a drugs and stem cell therapy, which enhance the neurological significantly reduced glucose-to-insulin ratio, demonstrating recovery, may be explored in the treatment of obesity. a decreased overall capability of disposing of ectogenic glucose. Another study by Yang et al. described that a sucrose-rich diet can cause a change in insulin, signaling by Conclusion the downregulation of genes involved in the insulin secretion. A sucrose diet produces obesity, which is similar to the There was a significant change in post-lesion values of TC, metabolic syndrome with insulin resistance and dyslipidemia, TG, and LDL and an insignificant rise in HDL and VLDL in and aVMH lesion further exaggerates it. Males are more both the control and experimental groups in females. Males prone to this exaggeration. Females seem to be protected to also showed similar results, except for TG which was higher some extent which may be because of the effect estrogen, in females. This suggests that the VMH lesion did not produce which needs further analysis. these effects, but may be because of a sucrose diet there are higher values in both the control and experimental groups. Acknowledgment This is in confirmation with a study by Yang et al., where the We thank JIPMER for providing the intramural research grant for measurement of hepatic TG clearly indicated an increased this study. hepatic lipid accumulation in response to the high-fat and high-sucrose diet as early as two weeks. This may be explained Author Contribution by the upregulation of genes involved in lipid metabolism and inflammation. The high triglyceridemia in the high-sucrose All authors have equally contributed. diet was because of an increased hepatic triacylglycerol secretion and a decreased removal of triacylglycerol from the Ethical Statement plasma in contrast to the high-fat-diet-induced triglyceridemia, Ethical clearance wasobtained before the start of experiment and all which is because of a decreased removal of triacylglycerol 23 procedures followed the CPCSEA guidelines. alone. Another study by Cao et al. observed that a modified high-sucrose diet produces hepatic lipidosis and hepatocyte 21 Declaration of Conflicting Interests mitochondrial swelling. To infer that sucrose diet creates a model of dyslipidemia. The authors declared no potential conflicts of interest with respect to Thyroid hormone is a major regulator of energy metabolism the research, authorship, and/or publication of this article. and food intake, greatly influencing the energy homeostasis of the body. In our study, the experimental group of females Funding showed a significant rise in T4 values, whereasthe experimental The conduct of this project was funded by the JIPMER intramural group of males showed a decrease in T3 values.The increasedT4 research fund. and decreased T3values in the experimental group of both the genders after lesion, may be because of the reduced conversion ORICD iD of T4 to T3. 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Published: Jan 1, 2021

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