Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency

Zhang, Yu; Gu, Ming; Cai, Wujie; Yu, Longquan; Li, Feng; Zhang, Lu; Zang, Qing-qing; Wang, Yahui; Wang, Dongshan; Chen, Hui; Tong, Qingchun; Ji, Guang; Huang, Cheng

doi:10.1038/srep19288

Cited by 64 publications

(50 citation statements)

References 45 publications

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“…Although no significant effect was seen in PGC-1α after UTS-001 (6 mg) treatment, PPARγ was significantly reduced. An increase in expression of PPARγ is one of the features of the steatotic liver and it is suggested that inhibiting the activity of PPARγ would be beneficial in the prevention of steatosis [ 53 ] and improving glucose metabolism [ 52 ]. PPAR γ is a likely target for small lipophilic compounds derived from endogenous metabolism and nutrition such as phospholipids [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of A Cargo-Less Liposomal Formulation on Dietary Obesity-Related Metabolic Disorders in Mice

Komalla

Sheikholeslami

et al. 2020

IJMS

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Current therapeutic options for obesity often require pharmacological intervention with dietary restrictions. Obesity is associated with underlying inflammation due to increased tissue macrophage infiltration, and recent evidence shows that inflammation can drive obesity, creating a feed forward mechanism. Therefore, targeting obesity-induced macrophage infiltration may be an effective way of treating obesity. Here, we developed cargo-less liposomes (UTS-001) using 1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC (synthetic phosphatidylcholine) as a single-agent to manage weight gain and related glucose disorders due to high fat diet (HFD) consumption in mice. UTS-001 displayed potent immunomodulatory properties, including reducing resident macrophage number in both fat and liver, downregulating liver markers involved in gluconeogenesis, and increasing marker involved in thermogenesis. As a result, UTS-001 significantly enhanced systemic glucose tolerance in vivo and insulin-stimulated cellular glucose uptake in vitro, as well as reducing fat accumulation upon ad libitum HFD consumption in mice. UTS-001 targets tissue residence macrophages to suppress tissue inflammation during HFD-induced obesity, resulting in improved weight control and glucose metabolism. Thus, UTS-001 represents a promising therapeutic strategy for body weight management and glycaemic control.

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Section: Discussionmentioning

confidence: 99%

Impact of A Cargo-Less Liposomal Formulation on Dietary Obesity-Related Metabolic Disorders in Mice

Komalla

Sheikholeslami

et al. 2020

IJMS

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“…ISOR has been reported to have various beneficial effects as an anti-oxidant [ 16 ], anti-inflammatory [ 17 ], anti-tumor [ 18 ], and anti-adipogenic [ 19 ] agent. A recent study reported that dietary ISOR is a PPARr antagonist that has protective effects against obesity and hepatic steatosis in diet-induced obese mice [ 20 ]. Lee and colleagues [ 19 ] indicated that ISOR inhibited adipogenesis through downregulation of PPAR-γ and CEBP-α in 3T3-L1 adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Effects of Isorhamnetin on Adipocyte Mitochondrial Biogenesis and AMPK Activation

Lee

Kim

2018

Molecules

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Isorhamnetin (ISOR), 3-O-methylquercetin, is a naturally occurring flavonoid in many plants. It is a metabolite derived from quercetin and is known to exert beneficial effects on the prevention of obesity. However, the molecular mechanism of action involved in ISOR-mediated mitochondrial biogenesis, and AMP-activated protein kinase (AMPK) activation in 3T3-L1 cells remains unclear. The aim of this study was to determine whether ISOR affected mitochondrial biogenesis and AMPK activation, during 3T3-L1 adipocyte differentiation. Intracellular lipid and triglyceride accumulation, and glycerol-3-phosphate dehydrogenase (GPDH) activity decreased in ISOR-treated cells. The mRNA levels of adipogenic genes, such as the proliferator-activated receptor-γ (PPAR-γ), and adipocyte protein 2 (aP2), were inhibited by ISOR. In contrast, mRNA levels of mitochondrial genes, such as peroxisome proliferator-activated reporter gamma coactivator-1α (PGC-1α), nuclear respiratory factor (NRF)-1, transcription factor A (Tfam), and carnitine palmitoyl transferase-1α (CPT-1α), were all stimulated by ISOR treatment. Mitochondria DNA (mtDNA) copy number and AMPK activity were also stimulated by ISOR. The results suggested that the mitochondrial biogenic effect of ISOR in adipocytes might have been associated with stimulation of mitochondrial gene expression, mtDNA replication, and AMPK activation.

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“…Leptin is a pivotal hormone regulating food intake and body weight by coordinating communications between the hypothalamus and the periphery. Leptin deficiency is a result of a genetic mutation predisposing subjects to severe obesity, while leptin resistance is linked to dietary obesity [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 41 ]. In this study, we found that obese 145E and HFD mice had lower circulating levels of IL-4 than wild-type and lean mice.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

Lin

Yang

Wang

et al. 2020

IJMS

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Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.

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Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency

Cited by 64 publications

References 45 publications

Impact of A Cargo-Less Liposomal Formulation on Dietary Obesity-Related Metabolic Disorders in Mice

Impact of A Cargo-Less Liposomal Formulation on Dietary Obesity-Related Metabolic Disorders in Mice

Effects of Isorhamnetin on Adipocyte Mitochondrial Biogenesis and AMPK Activation

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

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