Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles

The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.

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TM4SF5 Knockout Protects Mice from Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

10.2337/figshare.14831082.v1 ◽

2021 ◽

Author(s):

Cheoljun Choi ◽

Yeonho Son ◽

Jinyoung Kim ◽

Yoon Keun Cho ◽

Abhirup Saha ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Metabolism ◽

Metabolic Diseases ◽

Mammalian Target Of Rapamycin ◽

Regulatory Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Mtorc1 Signaling ◽

Mitochondrial Oxidative Metabolism

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. This study aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA-seq analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor alpha signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, our study demonstrated that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggested that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

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Non-Viable Lactobacillus johnsonii JNU3402 Protects against Diet-Induced Obesity

Foods ◽

10.3390/foods9101494 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1494

Author(s):

Garam Yang ◽

Eunjeong Hong ◽

Sejong Oh ◽

Eungseok Kim

Keyword(s):

Adipose Tissue ◽

Body Weight Gain ◽

Normal Diet ◽

The Body ◽

Peroxisome Proliferator ◽

Lactobacillus Johnsonii ◽

Peroxisome Proliferator Activated Receptor ◽

Diet Induced Obesity ◽

Brown Adipose ◽

And Function

In this study, the role of non-viable Lactobacillus johnsonii JNU3402 (NV-LJ3402) in diet-induced obesity was investigated in mice fed a high-fat diet (HFD). To determine whether NV-LJ3402 exhibits a protective effect against diet-induced obesity, 7-week-old male C57BL/6J mice were fed a normal diet, an HFD, or an HFD with NV-LJ3402 for 14 weeks. NV-LJ3402 administration was associated with a significant reduction in body weight gain and in liver, epididymal, and inguinal white adipose tissue (WAT) and brown adipose tissue weight in HFD-fed mice. Concomitantly, NV-LJ3402 administration to HFD-fed mice also decreased the triglyceride levels in the plasma and metabolic tissues and slightly improved insulin resistance. Furthermore, NV-LJ3402 enhanced gene programming for energy dissipation in the WATs of HFD-fed mice as well as in 3T3-L1 adipocytes with increased peroxisome proliferator-activated receptor-γ (PPARγ) transcriptional activity, suggesting that the PPARγ pathway plays a key role in mediating the anti-obesity effect of NV-LJ3402 in HFD-fed mice. Furthermore, NV-LJ3402 administration in HFD-fed mice enhanced mitochondrial levels and function in WATs and also increased the body temperature upon cold exposure. Together, these results suggest that NV-LJ3402 could be safely used to develop dairy products that ameliorate diet-induced obesity and hyperlipidemia.

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TM4SF5 Knockout Protects Mice from Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

10.2337/figshare.14831082 ◽

2021 ◽

Author(s):

Cheoljun Choi ◽

Yeonho Son ◽

Jinyoung Kim ◽

Yoon Keun Cho ◽

Abhirup Saha ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Metabolism ◽

Metabolic Diseases ◽

Mammalian Target Of Rapamycin ◽

Regulatory Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Mtorc1 Signaling ◽

Mitochondrial Oxidative Metabolism

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Clinical Application Potential of Small Molecules that Induce Brown Adipose Tissue Thermogenesis by Improving Fat Metabolism

Cell Transplantation ◽

10.1177/0963689720927394 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092739

Author(s):

Kang-Yun Lu ◽

Kingsley Theras Primus Dass ◽

Sheng-Feng Tsai ◽

Hong-Meng Chuang ◽

Shinn-Zong Lin ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Adenosine Monophosphate ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Computed Tomography Images ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Treatment Of Obesity

Mammalian fat comprises white and brown adipose tissue (WAT and BAT, respectively). WAT stores energy, whereas BAT is used for thermogenesis. In recent years, the incidence of obesity and its associated disorders have increased tremendously. Considering the thermogenic capacity and decreased levels of BAT with increasing age, BAT can be used as a suitable therapeutic target for the treatment of obesity and diabetes. In several studies, using positron emission tomography and computed tomography images, adult humans have been shown to have functional BAT in interscapular fat. Results of these basic research studies on BAT have shed light on the new components of transcriptional regulation and the role of hormones in stimulating BAT growth and differentiation. In this review article, we have summarized the thermogenic regulators identified in the past decades by focusing on peroxisome proliferator-activated receptor gamma/uncoupling protein 1 activators, branched-chain amino acids, fatty acids (lipokine), and adenosine monophosphate-activated protein kinase mediators. We have also presented the progress of a few ongoing clinical trials aimed at the treatment of obesity and its associated metabolic disorders. The main purpose of this review was to provide a comprehensive introduction to the latest knowledge of the representative thermogenic regulators for the treatment of obesity. The fat combustion capacity of BAT may have great potential and can be considered as a suitable target for the therapeutic application of drugs from bench-to-bed treatment of obesity and the associated diseases.

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C333H Ameliorated Insulin Resistance through Selectively Modulating Peroxisome Proliferator-Activated Receptor γ in Brown Adipose Tissue of db/db Mice

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b13-00008 ◽

2013 ◽

Vol 36 (6) ◽

pp. 980-987 ◽

Cited By ~ 6

Author(s):

Ning Zhang ◽

Wei Chen ◽

Xinbo Zhou ◽

Xiaolin Zhou ◽

Xinni Xie ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v1 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract BackgroundPrescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant sedation, weight gain, and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.MethodsTo investigate the efficacy of interventions of statin aimed at reversing SGA-induced dyslipidemia, young Sprague Dawley (SD) rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks.ResultsOlanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but had no significant effect on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. A down-regulating of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) expression was observed in brown adipose tissue (BAT) in the olanzapine-only group, following a significant decrease in the ratio of phosphorylated PKA (p-PKA)/PKA. Interestingly, these protein changes could be reversed by co-treatment with O+B. Our results demonstrated simvastatin to be effective in ameliorating TC and TG elevated by olanzapine.ConclusionsModulation of BAT activity could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v4 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract Background Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.Methods To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks. Results Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by co-treatment with O+B. Conclusions Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Cells ◽

10.3390/cells8080831 ◽

2019 ◽

Vol 8 (8) ◽

pp. 831 ◽

Cited By ~ 1

Author(s):

Virag Vas ◽

Tamás Háhner ◽

Gyöngyi Kudlik ◽

Dávid Ernszt ◽

Krisztián Kvell ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Growth Factor Receptor ◽

Cellular Level ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Kinase Substrate ◽

Downstream Signaling ◽

Brown Adipose ◽

Morphological Differences

Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.

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Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Endocrinology ◽

10.1210/en.2011-1339 ◽

2012 ◽

Vol 153 (1) ◽

pp. 113-122 ◽

Cited By ~ 23

Author(s):

Shoba Shetty ◽

Maria A. Ramos-Roman ◽

You-Ree Cho ◽

Jonathan Brown ◽

Jorge Plutzky ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Uncoupling Protein ◽

Retinol Binding Protein ◽

Peroxisome Proliferator ◽

Tissue Mass ◽

Triglyceride Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

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Effect of Linseed Oil Dietary Supplementation on Fatty Acid Composition and Gene Expression in Adipose Tissue of Growing Goats

BioMed Research International ◽

10.1155/2013/194625 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

M. Ebrahimi ◽

M. A. Rajion ◽

Y. M. Goh ◽

A. Q. Sazili ◽

J. T. Schonewille

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

Subcutaneous Adipose Tissue ◽

Linseed Oil ◽

Control Group ◽

Peroxisome Proliferator ◽

Potential Health ◽

Peroxisome Proliferator Activated Receptor ◽

Subcutaneous Adipose

This study was conducted to determine the effects of feeding oil palm frond silage based diets with added linseed oil (LO) containing highα-linolenic acid (C18:3n-3), namely, high LO (HLO), low LO (LLO), and without LO as the control group (CON) on the fatty acid (FA) composition of subcutaneous adipose tissue and the gene expression of peroxisome proliferator-activated receptor (PPAR)α, PPAR-γ, and stearoyl-CoA desaturase (SCD) in Boer goats. The proportion of C18:3n-3 in subcutaneous adipose tissue was increased (P<0.01) by increasing the LO in the diet, suggesting that the FA from HLO might have escaped ruminal biohydrogenation. Animals fed HLO diets had lower proportions of C18:1 trans-11, C18:2n-6, CLA cis-9 trans-11, and C20:4n-6 and higher proportions of C18:3n-3, C22:5n-3, and C22:6n-3 in the subcutaneous adipose tissue than animals fed the CON diets, resulting in a decreased n-6:n-3 fatty acid ratio (FAR) in the tissue. In addition, feeding the HLO diet upregulated the expression of PPAR-γ(P<0.05) but downregulated the expression of SCD (P<0.05) in the adipose tissue. The results of the present study show that LO can be safely incorporated in the diets of goats to enrich goat meat with potential health beneficial FA (i.e., n-3 FA).

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