• BMB Reports
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• 제51권1호
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• pp.39-44
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• 2018

Exchange protein directly activated by cAMP (Epac) 2a-knockout (KO) mice exhibit accelerated diet-induced obesity and are resistant to leptin-mediated adipostatic signaling from the hypothalamus to adipose tissue, with sustained food intake. However, the impact of Epac2a deficiency on hypothalamic regulation of sympathetic nervous activity (SNA) has not been elucidated. This study was performed to elucidate the response of Epac2a-KO mice to dexamethasone-induced muscle atrophy and acute cold stress. Compared to age-matched wild-type mice, Epac2a-KO mice showed higher energy expenditures and expression of myogenin and uncoupling protein-1 in skeletal muscle (SM) and brown adipose tissue (BAT), respectively. Epac2a-KO mice exhibited greater endurance to dexamethasone and cold stress. In wild-type mice, exogenous leptin mimicked the responses observed in Epac2a-KO mice. This suggests that leptin-mediated hypothalamic signaling toward SNA appears to be intact in these mice. Hence, the potentiated responses of SM and BAT may be due to their high plasma leptin levels.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2003년도 Annual Meeting of KSAP : International Symposium on Pharmaceutical and Biomedical Sciences on Obesity
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• pp.3-4
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• 2003

Body weight is maintained at a relatively constant level over days and months despite variability in food intake and physical activity. To achieve energy homeostasis, the hypothalamus receives information related to energy surplus or shortage from the periphery and controls food intake and energy expenditure. Leptin, an adipocyte derived hormone, is a principal mediator that signals the brain about the stored energy status. Increased leptin signaling in the brain prevents excess energy stores by suppressing food intake and increasing energy expenditure. In addition, insulin and nutrients themselves, such as glucose and free fatty acids, also regulate food intake.

• BMB Reports
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• 제48권12호
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• pp.647-654
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• 2015

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

• Clinical and Experimental Pediatrics
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• 제51권6호
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• pp.597-603
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• 2008

목 적 : 비만은 지방세포의 축적과 인슐린 내성으로 제 2형 당뇨병을 초래하고, 고 인슐린혈증과 고혈당이 염증 과정의 전구 물질과 함께 작용하여 혈관 내피의 이상, 혈청 지질의 이상, 고혈압과 혈관 염증을 일으켜 동맥경화와 심혈관 질환을 야기하는 것으로 알려져 왔다. Leptin은 adiopnectin과 함께 지방 세포로부터 생산되는 가장 풍부한 adipocytokine으로서, 일차적으로는 식욕 조절과 체내 지방 축적 조절의 기능을 하지만, IL-6, IL-12, TNF-${\alpha}$와 같은 다른 사이토카인과 함께 염증과정의 전구 물질이 되며 여러 면역 관련 질환에서 중요한 매개체가 된다. 이번 연구에서는 비만 청소년에서 leptin과 여러 cytokine과의 상관관계를 알아보고자 하였다. 방 법 : 16세 이상부터 18세 미만의 66명의 중등도 이상의 비만 청소년을 대상군으로 하였고, 같은 연령의 정상 청소년 26명을 대조군으로 하였다. 신장, 체중을 이용하여 비만도와 체질량지수를 산출하였고, 혈청 지질, 간 효소치를 측정하였다. 효소면역 측정법을 이용하여 IL-6, TNF-${\alpha}$를 측정하였고, 방사면역 측정법을 이용하여 adiponectin, leptin, 인슐린을 측정하였다. 이 후 leptin과 각 측정치와의 상관성을 알아보았다. 결 과 : Leptin은 비만군에서 대조군보다 유의하게 높았고, TNF-${\alpha}$와 IL-6도 비만군에서 대조군보다 유의하게 높았다. 인슐린도 비만군에서 대조군보다 유의하게 높았고 adiponectin은 비만군에서 유의하게 낮았다. Leptin은 비만도, 체질량지수, IL-6과 유의한 양의 상관관계를 보였으며, 또한 IL-6와 TNF-${\alpha}$간에 유의한 양의 상관관계를 보였다. 결 론 : 비만 청소년에서 leptin, TNF-${\alpha}$, IL-6와 같은 cytokine과 insulin이 성인병으로 진행되는데 중요한 요소가 될 것이며, leptin을 성인병의 예측 인자 및 임상치료의 척도로 사용하기 위해 더 많은 연구가 필요할 것으로 생각된다.

• 동의생리병리학회지
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• 제21권1호
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• pp.86-92
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• 2007

Hibiscus sabdariffa L., a tropical beverage material, is used commonly as in folk medicine against hypertension, pyrexia, inflammation, liver disorders, and obesity. However, the mechanism by which Hibiscus sabdariffa L. modulates adipogenic differentiation is remained to be elusive. This report was designed to investigate the inhibitory effect of Hibiscus extract on insulin signaling pathway during adipocyte differentiation in 3T3-L1 preadipocytes. 3T3-L1 preadipocytes were differentiated with isobutylmethylxanthine, dexamethasone, and insulin (MDI) and followed by the addition of Hibiscus extract. Treatment with Hibiscus resulted in a decrease of lipid droplet accumulation, which was suppressed by PI-3 kinase inhibitor wortmannin in 3T3-L1 preadipocytes. Also, Hibiscus extract markedly attenuated the mRNA expression of adipogenic transcriptional factor PPAR${\gamma}$ and adipogenic hormon Leptin during adipogenesis. However, it did not affect the expression of adiponectin in 3T3-L1 preadipocytes differentiated with MDI mixture. Furthermore, Adipogenic differentiation by MDI mixture increased the phosphorylation and expression of PI3-Kinase and Akt in 3T3 preadipocytes, which was markedly suppressed by Hibiscus extract treatment. Taken together, our results suggest that Hibiscus extract suppressed the adipogenic differentiation of 3T3 preadipocytes through activation of PI3-Kinase and Akt signaling pathway.

• 생명과학회지
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• 제25권3호
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• pp.285-292
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• 2015

본 연구에서는 3T3-L1 지방전구세포가 지방세포로 분화되는 과정에서 진피 에탄올 추출물(ethanol extracts of citrus peel, EECP)이 유발하는 항비만 효능에 대해서 조사하였다. 3T3-L1 세포의 생존율 및 증식에 영향을 미치지 않는 농도의 EECP를 처리하였을 경우 지방세포에서 특징적으로 나타나는 lipid droplet의 형성과 triglyceride의 생성도 억제되는 것으로 나타났다. EECP가 유발하는 지방세포로의 분화억제에는 PPARγ, C/EBPα, C/EBPβ 및 SREBP-1c 등과 같은 adipogenic transcription factors의 발현억제가 관여하는 것으로 나타났으며, 그 결과로 aP2 및 Leptin과 같은 adipocyte expressed genes의 발현도 억제되는 것으로 조사되었다. 또한 EECP는 AMPK 및 ACC의 인산화를 유발하였으며, AMPK 억제제인 Compound C를 이용하여 AMPK의 활성을 억제하였을 경우 EECP에 의한 AMPK의 인산화와 adipogenic transcription factors의 억제현상이 회복되었다. 이상의 결과에서 EECP는 AMPK signaling pathway를 통하여 항비만 효능을 가진다는 것을 알 수 있었으며, 향후 비만 예방 및 억제와 관련된 기능성 소재로서의 진피의 활용 가능성을 제시한 것으로서 그 가치가 매우 높을 것으로 생각된다.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.186-196
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• 2023

Dyglomera^® is an aqueous ethanol extract derived from the fruit and pods of Dichrostachys glomerata. A previous study has revealed that Dyglomera regulates adipogenesis and lipolysis by modulating AMP-activated protein kinase (AMPK) phosphorylation and increased expression levels of lipolysis-related proteins in white adipose tissue of high fat diet-induced mice and 3T3-L1 adipocyte cells. To further investigate mechanisms of Dyglomera, additional studies were performed using 3T3-L1 cells. Results revealed that Dyglomera downregulated adipogenesis by inhibiting the protein kinase B/mammalian target of rapamycin signaling pathway and reconfirmed that it downregulated gene expression levels of proliferator-activated receptor (PPAR)-γ, CCAAT enhancer binding protein α, sterol-regulation element-binding protein-1c. Dyglomera also reduced adipokines such as tumor necrosis factor alpha, interleukin-1β, and interleukin 6 by regulating leptin expression. Moreover, Dyglomera promoted beige-and-brown adipocyte-related phenotypes and regulated metabolism by increasing mitochondrial number and expression levels of genes such as T-box protein 1, transmembrane protein 26, PR domain 16, and cluster of differentiation 40 as well as thermogenic factors such as uncoupling protein 1, proliferator-activated receptor-gamma co-activator-1α, Sirtuin 1, and PPARα through AMPK activation. Thus, Dyglomera not only can inhibit adipogenesis, but also can promote lipolysis and thermogenesis and regulate metabolism by affecting adipokine secretion from 3T3-L1 adipocytes.

• Asian Pacific Journal of Cancer Prevention
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• 제16권10호
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• pp.4161-4168
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• 2015

Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression).

• 생명과학회지
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• 제33권3호
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• pp.287-294
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• 2023

건강한 adipose tissue는 대사 항상성 통해 비만을 막는데 중요하다고 할 수 있다. Adipose tissue는 포도당과 지질 대사를 통해 에너지 균형에 중요한 역할을 한다. 영양분 상태에 따라, adipose tissue는 지질을 저장하여 커지기도 하고, 지질 분해를 통해 에너지를 소비하기도 한다. 게다가, adipose tissue는 호르몬 분비기관으로 작용이 부각되고 있다. 다양한 adipose tissue 호르몬이 존재하며, metabolic signaling을 통해 다른장기와 조직에 영향을 준다. 예를 들면, adipose tissue에서 분비하는 대표적인 펩타이드 호르몬(adipokine)은 섭식조절을 위해 뇌의 중추신경을 자극한다. 또한 adipocytes도 염증성 cytokines을 분비하여 adipose tissue의 immune cells을 표적으로 한다. 당연하게도, adipocytes는 지질에서 만들어지는 호르몬(lipokine)이 분비되어 특정 수용체와 결합하여 paracrine 및 endocrine으로 영향을 준다. 이러한 adipose tissue 호르몬에 의한 장기 조직 간의 상호작용을 이해하기 위해서는, 세부적인 adipocytes 및 다른 표적 세포에서 metabolic sig- naling이 규명되어야 한다. 그러므로, 과체중이나 비만의 건강하지 못한 adipose tissue에서는 metabolic sig- naling의 비정상적인 조절이 일어난다고 할 수 있다. 새로운 adipose metabolic signaling을 표적으로 하는 치료제는 항 비만 약물개발을 이끌어 낼 수 있다. 본 총설논문은 비만과 대사질환 관점에서 adipose tissue 호르몬과 metabolic signaling의 최신 연구결과를 요약 정리한다.

• The Korean Journal of Physiology and Pharmacology
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• 제20권6호
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• pp.581-593
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• 2016

The advantages of monounsaturated fatty acids (MUFAs) on insulin resistance and type 2 diabetes mellitus (T2DM) have been well established. However, the molecular mechanisms of the anti-diabetic action of MUFAs remain unclear. This study examined the anti-hyperglycemic effect and explored the molecular mechanisms involved in the actions of fish oil- rich in MUFAs that had been acquired from hybrid catfish (Pangasius larnaudii${\times}$Pangasianodon hypophthalmus) among experimental type 2 diabetic rats. Diabetic rats that were fed with fish oil (500 and 1,000 mg/kg BW) for 12 weeks significantly reduced the fasting plasma glucose levels without increasing the plasma insulin levels. The diminishing levels of plasma lipids and the muscle triglyceride accumulation as well as the plasma leptin levels were identified in T2DM rats, which had been administrated with fish oil. Notably, the plasma adiponectin levels increased among these rats. The fish oil supplementation also improved glucose tolerance, insulin sensitivity and pancreatic histological changes. Moreover, the supplementation of fish oil improved insulin signaling ($p-Akt^{Ser473}$ and p-PKC-${\zeta}/{\lambda}^{Thr410/403}$), $p-AMPK^{Thr172}$ and membrane GLUT4 protein expressions, whereas the protein expressions of pro-inflammatory cytokines (TNF-${\alpha}$ and nuclear NF-${\kappa}B$) as well as p-PKC-${\theta}^{Thr538}$ were down regulated in the skeletal muscle. These data indicate that the effects of fish oil-rich in MUFAs in these T2DM rats were partly due to the attenuation of insulin resistance and an improvement in the adipokine imbalance. The mechanisms of the anti-hyperglycemic effect are involved in the improvement of insulin signaling, AMPK activation, GLUT4 translocation and suppression of pro-inflammatory cytokine protein expressions.