Abstract 17361: How Leptin Harms the Heart in High Fat Diet-Induced Obesity

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Maria Pini

Introduction: Sedentary lifestyle and excessive calorie intake are risk factors for CVD. We have demonstrated the cardioprotective effect of exercise in aged mice and the critical role of visceral adiposity and its profibrotic secretome in increasing cardiovascular risks in obesity and aging. The association between exercise, lowered plasma leptin and reduced inflammatory leukocytes has been recently shown in patients with atherosclerosis. It remains unclear whether elevated plasma leptin can preserve or alter cardiovascular function in obesity. Methods: We analyzed the effect of high fat diet (HFD) in C57BL/6J male mice on the heart in terms of function, structure, histology and key molecular markers. Two interventions were used: 1) active fat mass loss via exercise (daily swimming) during HFD; 2) passive fat mass loss via surgical removal of the visceral adipose tissue (VAT lipectomy) followed by HFD. Results: HFD increased body weight and adiposity, leading to higher plasma leptin, glucose and insulin levels, compared to control diet (CD) mice. HFD impaired left ventricle (LV) structure (hypertrophy, interstitial fibrosis) and cardiac function (echocardiography, in vivo hemodynamics). Atria of HFD mice had enhanced pro-inflammatory protein production. Exercise reduced circulating leptin levels in HFD mice by 50%, in line with fat mass loss. In contrast, lipectomy reduced visceral fat mass, but body weight, adiposity and plasma leptin did not change. Both exercise and VAT lipectomy improved cardiac contractility, reversed collagen deposition and oxidative stress in HFD mice. Both interventions downregulated LV pro-inflammatory markers. We proved the role of leptin in cardiac remodeling in vitro by incubating primary cardiac fibroblasts with hyperleptinemic plasma from HFD mice. Remarkably, plasma from HFD-EX (exercise) suppressed the fibro-proliferative and pro-inflammatory responses of cardiac fibroblasts. Conclusions: Leptin directly contribute to cardiac fibrosis in obesity via activation and proliferation of cardiac fibroblasts. Understanding how leptin signals to the heart might have implications in a wide range of CVD, potentially helping early stratification and personalized care.

1997 ◽  
Vol 273 (1) ◽  
pp. R113-R120 ◽  
Author(s):  
B. Ahren ◽  
S. Mansson ◽  
R. L. Gingerich ◽  
P. J. Havel

Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin.


Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2333-2345 ◽  
Author(s):  
Minglan Yang ◽  
Maopei Chen ◽  
Jiqiu Wang ◽  
Min Xu ◽  
Jichao Sun ◽  
...  

A growing body of epidemiological research show that Bisphenol A (BPA) is positively correlated with obesity and metabolic disorders. However, the mechanisms of BPA on adiposity remain largely unknown. In this study, we found that 5-week-old male and female C57BL/6J mice exposed to four dosages of BPA (5, 50, 500, and 5000 μg/kg/d) by oral intake for 30 days showed significantly increased body weight and fat mass in a nonmonotonic dose-dependent manner when fed a chow diet. The effect occurred even at the lowest concentration (5μg/kg/d), lower than the tolerable daily intake of 50 μg/kg/day for BPA. However, no significant difference in body weight and fat mass was observed in either male or female mice fed a high-fat diet, suggesting that BPA may interact with diet in promoting obesity risk. In vitro study showed that BPA treatment drives the differentiation of white adipocyte progenitors from the stromal vascular fraction, partially through glucocorticoid receptor. BPA exposure increased circulating inflammatory factors and the local inflammation in white adipose tissues in both genders fed a chow diet, but not under high-fat diet. We further found that BPA concentration was associated with increased circulating inflammatory factors, including leptin and TNFα, in lean female subjects (body mass index &lt; 23.0 kg/m2) but not in lean male subjects or in both sexes of overweight/obese subjects (body mass index &gt; 25.0 kg/m2). In conclusion, we demonstrated the nonmonotonic dose effects of BPA on adiposity and chronic inflammation in 5-week-old mice, which is related to caloric uptake.


2017 ◽  
Vol 313 (5) ◽  
pp. R535-R548 ◽  
Author(s):  
Jonathan Weng ◽  
Danwen Lou ◽  
Stephen C. Benoit ◽  
Natalie Coschigano ◽  
Stephen C. Woods ◽  
...  

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.


2016 ◽  
Vol 3 (3) ◽  
pp. 202-206
Author(s):  
Thatit Nurmawati

Cholesterol is an essential substance for the body. The role of cholesterol as material hormones,cell membranare needed by the body. This conditionchanges into a distrubtion if the cholesterollevels in the blood increase. Weight becomes one of this trigger. The consumption of high-fat foodsincrease weight which resulting in the increase of cholesterol cases. The purpose of this study was todetermine the level of correlations between weight and cholesterol levels after being given a high-fatdiet.The study used rats (Rattus norvegicus) sex male, 16 rats with age between 1-2 months. Rats weightrange between 100-150 gr and in healthy conditions. The giving of high-fat diet were in the form ofchicken feed, duck eggs, goat oil, lard and flour for 8 weeks. The data measurement done by scales andmeasuringcholesterol levels through the end of the tail by means of easy touch. The data analysis weredone to understand level of correlation between variables. The presentation of the data used tables. Theresults showed body weight of rats did not change after administration of a high-fat diet. The cholesterolslevels of the subjects were high. Theadministration of high-fat diet from egg yolk dan goat oilcouldincrease the level of cholesterol. There was a correlation between weight and cholesterol levels afterbeing given a high-fat diet (p <0.5). It was needed to repeatthe measurements to determine changes incholesterol levels and other factors that affect thigh blood to cholesterol levels.


2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Manisha Gupte ◽  
Samvruta Tumuluru ◽  
Anand P Singh ◽  
Prachi Umbarkar ◽  
Qinkun Zhang ◽  
...  

Introduction: Previous studies from our group have demonstrated that cardiac myocyte glycogen synthase kinase-3’s (GSK-3) are required to maintain normal cardiac physiology. Adult mice lacking both isoforms of GSK-3 (α and β) in cardiac myocytes exhibit excessive dilatative remodeling and ventricular dysfunction ultimately leading to death. While high fat diet (HFD) induced obesity is associated with increased risk of cardiovascular disease, the specific role of cardiac GSK-3α or GSK-3β in obesity-associated cardiac dysfunction is unknown. Objective: The primary goal of the present study was to investigate the role of cardiomyocyte GSK-3β in cardiac homeostasis in HFD-induced chronic obesity model. Method: Cardiomyocyte specific-GSK-3β knock out (CM-GSK-3βKO) and wild type (WT) mice were fed either a chow (11.5% calories from fat) or high-fat (60% calories from fat) for 24 weeks. Cardiac function was accessed by non-invasive transthoracic echocardiography. Results: HFD significantly increased body weight, lean and fat mass in the WT and CM-GSK-3βKO compared to chow. However, there was no difference in body weights, lean and fat mass between the two genotypes fed either a chow or HFD. Furthermore, ventricular chamber dimensions and cardiac function were comparable between the WT and CM-GSK-3βKO mice fed a chow diet. In contrast, high fat fed CM-GSK-3βKO hearts exhibit significant cardiac hypertrophy (heart weight/tibia length ratio) and ventricular dysfunction (reduced ejection fraction (EF) and fractional shortening (FS)) compared to the WT. Interestingly cardiomyocytes from HF fed CM-GSK-3βKO exhibit structural abnormalities and increased expression of pro-apoptotic protein Bax and reduced expression of Bcl-2, an anti-apoptotic protein. Conclusion: In summary, these data suggests that cardiac GSK-3β is important in the setting of HFD-induced chronic obesity to maintain cardiac function. In the absence of GSK-3β, cardiomyocytes undergo morphometric abnormalities, excessive fat infiltration and apoptosis leading to cardiac dysfunction.


2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1126-1126
Author(s):  
Weimin Guo ◽  
Dayong Wu ◽  
Lijun Li ◽  
Edwin Ortega ◽  
Yankun Liu ◽  
...  

Abstract Objectives Obesity is associated with impaired immune function. However, impact of obesity on blood T cell profile is not well studied. The objectives of this study were to investigate the effects of high fat diet (HFD)-induced obesity and long-term fruits and vegetable (FV) consumption on body composition and blood T cell profile. Methods This is partial report from an ongoing study. A total of 240 male C57BL/6J mice were randomly assigned to 4 groups: low fat control (LF-C) or high-fat control (HF-C) diet alone, or together with 15% of a unique mixture of FV (w/w, equivalent to 7–9 servings F&V/d for human) (LF-FV or HF-FV). The feeding will continue until 50% mortality is reached in one group. Body weight, body composition (using MRI), and blood T cell profile (using FACS) are monitored longitudinally at different time points. The results reported here are those assessed when mice were 7 months old. Results After 7 months of feeding, mice fed HF-C gained more weight compared to those fed LF-C. Mice fed HF-FV or LF-FV diets had significantly reduced weight gain and fat mass, and higher muscle mass compared to those fed HF-C or LF-C diet, respectively. Mice fed HF-C also had significantly lower percentage of blood CD3+, CD4+, and CD8 + T cells compared with the LF-C. FV supplementation prevented HFD-induced decrease in percentage of CD3+ and CD4+ cells. Furthermore, both % CD3+ and CD4+ cells were negatively correlated with body weight (P &lt; 0.001) or percentage of fat mass (P &lt; 0.001), and positively associated with percentage of lean mass (P &lt; 0.001). Conclusions Our results suggest that consuming large amounts of a unique mixture of F&V curbs HFD-induced body weight gain, reduces fat mass, and favorably affects blood T cell population. Ongoing studies will assess these analytes when mice are 16 months old, and again when one group reaches 50% mortality, and determine their correlations with functional measures of T cell response, host resistance to infection, health span, and mortality. Funding Sources This study was supported by the U.S. Department of Agriculture – Agricultural Research Service (ARS), under Agreement No. 58–1950-4–004.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yaoli Liu ◽  
Xiazhou Fu ◽  
Zhiyong Chen ◽  
Tingting Luo ◽  
Chunxia Zhu ◽  
...  

Background: Sulforaphane (SFN), an isothiocyanate naturally occurring in cruciferous vegetables, is a potent indirect antioxidant and a promising agent for the control of metabolic disorder disease. The glucose intolerance and adipogenesis induced by diet in rats was inhibited by SFN. Strategies aimed at induction of brown adipose tissue (BAT) could be a potentially useful way to against obesity. However, in vivo protective effect of SFN against obesity by browning white adipocyte has not been reported. Our present study is aimed at evaluation the efficacy of the SFN against the high-fat induced-obesity mice and investigating the potential mechanism.Methods: High-Fat Diet-induced obese female C57BL/6 mice were intraperitoneally injected with SFN (10 mg/kg) daily. Body weight was recorded every 3 days. 30 days later, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed. At the end of experiment, fat mass were measured and the adipogenesis as well as browning associated genes expression in white adipose tissue (WAT) were determined by RT-qPCR and western blot. Histological examination of the adipose tissue samples were carried out with hematoxylin–eosin (HE) staining and immunofluorescence staining method. In vitro, pre-adipocytes C3H10T1/2 were treated with SFN to investigate the direct effects on adipogenesis.Results: SFN suppressed HFD-induced body weight gain and reduced the size of fat cells in mice. SFN suppressed the expression of key genes in adipogenesis, inhibited lipid accumulation in C3H10T1/2 cells, increased the expression of brown adipocyte-specific markers and mitochondrial biogenesis in vivo and in vitro, and decreased cellular and mitochondrial oxidative stress. These results suggested that SFN, as a nutritional factor, has great potential role in the battle against obesity by inducing the browning of white fat.Conclusion: SFN could significantly decrease the fat mass, and improve glucose metabolism and increase insulin sensitivity of HFD-induced obese mice by promoting the browning of white fat and enhancing the mitochondrial biogenesis in WAT. Our study proves that SFN could serve as a potential medicine in anti-obesity and related diseases.


2021 ◽  
Vol 8 (3) ◽  
pp. 179-189
Author(s):  
Anil Kumar ◽  
Anand Acharya ◽  
Subhadra Devi Velichety ◽  
Rajesh Vaderav

Diet rich in fat is one of the main risk factor for the development of Alzheimer’s disease. Studies have shown that diet rich in fat disrupts memory and learning. The present study evaluates the ameliorative role of Ginkgobiloba and Rosuvastatin against high fat diet induced neurotoxicity in CA1 (Corona Ammonis) region of hippocampus. Animals were randomly divided into six groups. Group I received normal diet, Group II received high fat diet, Group III & IV were treated with Ginkgobiloba 50mg/kg and 100mg/kg body weight, and Group V & VI were treated with Rosuvastatin 10mg/kg and 20 mg/kg body weight. All the rats were subjected to spatial learning (Morris water maze). Subsequently, rats were sacrificed and brains were removed. Golgi staining was done and CA1 neurons of hippocampus were traced using camera lucida. Dendritic branching points and dendritic intersections were quantified. Lipid profile and Super oxide (SOD) was also estimated.There was enhancement of spatial learning in treatment group rats. Furthermore, a significant increase in dendritic length and branching points was observed in CA1 region along with significant decrease in the Superoxide dismutase in rats treated with higher dose of Ginkgobiloba and Rosuvastatin. Present study concludes that Ginkgobiloba and Rosuvastatin in higher dose have protective role against high fat diet induced neurotoxicity in CA1 region.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2421-2421
Author(s):  
Constance Tom Noguchi ◽  
Heather Marie Rogers

Erythropoietin (EPO) promotes erythroid differentiation and increases glucose uptake in erythroid progenitor cells in culture. The metabolic burden associated with EPO treatment in adult mice is suggested by a decrease in body weight concomitant with increased hematocrit. Wild type male mice (C57Bl/6, age 8 months) treated with EPO showed the expected increase in hematocrit accompanied by a fall in blood glucose level and a decrease in body weight and fat mass. However, the decrease in body weight is even more evident in obese mice on a high fat diet and has also been linked to non-hematopoietic response, particularly with EPO receptor (EpoR) expression in white adipose tissue. We examined the metabolic burden of EPO treatment (3000U/kg for 3 weeks) in young, lean male mice (3 months) placed on high fat diet at the time of EPO administration. The increase in hematocrit was accompanied by decreased blood glucose level and improved glucose tolerance. However, no difference in body weight was observed between mice treated with EPO and the saline treated group, suggesting that the EPO stimulated decrease in body weight is evident primarily in older animals with greater fat mass. To determine the contribution of EpoR expression in non-hematopoietic tissue to the metabolic EPO response, young male mice with EpoR restricted to erythroid tissue (TgEpoR) were placed on high fat diet and treated with EPO. The expected increased hematocrit was also accompanied by decreased blood glucose level and improved glucose tolerance, and no change in body weight between EPO and saline treatment. The similar responses observed in young wild type and TgEpoR mice suggest that the EPO stimulated increase in glucose metabolism is associated with increased erythropoiesis rather than a direct EPO response in non-hematopoietic tissue. TgEpoR mice exhibit an age dependent increase in fat mass even greater than that observed in wild type mice, and by 8 months TgEpoR mice are obese, glucose intolerant and insulin resistant compared with wild type mice. At 8 months, TgEpoR mice treated with EPO show the increase in hematocrit and, despite the increase in fat mass, there is only a minimal decrease in body weight compared with wild type mice. These data provide evidence that in addition to the age dependent association of EPO stimulated decrease in body weight and fat mass, this decrease in body weight is due largely to EPO response related to EpoR expression in non-hematopoietic tissue. Interestingly, young male mice with targeted deletion of EpoR in adipose tissue placed on a high fat diet and treated with EPO show the increase in hematocrit and improvement in glucose tolerance, and at 8 months, the increase in hematocrit with EPO treatment is accompanied by minimal change in body weight. The similar metabolic response of these mice with targeted deletion of EpoR in adipose tissue to TgEpoR mice indicate the contribution of EpoR expression in adipose tissue to the loss of body weight and fat mass. Therefore, the metabolic burden associated with EPO stimulated erythropoiesis appears to be reflected in improved glucose metabolism and glucose tolerance with minimal or no effect on body weight, is evident in young, lean mice, and is independent of EpoR expression in non-hematopoietic tissue. In older mice, non-hematopoietic metabolic EPO response is more readily apparent as reflected in loss of body weight/fat mass, which overshadows the erythropoietic metabolic response. In combination, the metabolic response to EPO treatment results from EPO stimulated increased erythropoiesis, improved glucose metabolism and glucose tolerance, and an age dependent decrease in body weight and fat mass associated with EpoR expression in non-hematopoietic tissue, particularly in white adipose tissue. Disclosures No relevant conflicts of interest to declare.


Sign in / Sign up

Export Citation Format

Share Document