Glucose and Insulin Stimulate Lipogenesis in Porcine Adipocytes: Dissimilar and Identical Regulation Pathway for Key Transcription Factors

Zhang, Guo Hua,Lu, Jian Xiong,Chen, Yan,Dai, Hong Wei,ZhaXi, YingPai,Zhao, Yong Qing,Qiao, Zi Lin,Feng, Ruo Fei,Wang, Ya Ling,Ma, Zhong Ren Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.11

Lipogenesis is under the concerted action of ChREBP, SREBP-1c and other transcription factors in response to glucose and insulin. The isolated porcine preadipocytes were differentiated into mature adipocytes to investigate the roles and interrelation of these transcription factors in the context of glucose- and insulin-induced lipogenesis in pigs. In ChREBP-silenced adipocytes, glucose-induced lipogenesis decreased by ~70%, however insulin-induced lipogenesis was unaffected. Moreover, insulin had no effect on ChREBP expression of unperturbed adipocytes irrespective of glucose concentration, suggesting ChREBP mediate glucose-induced lipogenesis. Insulin stimulated SREBP-1c expression and when SREBP-1c activation was blocked, and the insulin-induced lipogenesis decreased by ~55%, suggesting SREBP-1c is a key transcription factor mediating insulin-induced lipogenesis. $LXR{\alpha}$ activation promoted lipogenesis and lipogenic genes expression. In ChREBP-silenced or SREBP-1c activation blocked adipocytes, $LXR{\alpha}$ activation facilitated lipogenesis and SREBP-1c expression, but had no effect on ChREBP expression. Therefore, $LXR{\alpha}$ might mediate lipogenesis via SREBP-1c rather than ChREBP. When ChREBP expression was silenced and SREBP-1c activation blocked simultaneously, glucose and insulin were still able to stimulated lipogenesis and lipogenic genes expression, and $LXR{\alpha}$ activation enhanced these effects, suggesting $LXR{\alpha}$ mediated directly glucose- and insulin-induced lipogenesis. In summary, glucose and insulin stimulated lipogenesis through both dissimilar and identical regulation pathway in porcine adipocytes.

Transcriptional Regulation of Lipogenesis and Adipose Expansion

장영훈 한국생명과학회 2022 생명과학회지 Vol.32 No.4

PPARγ and C/EBPα are master adipogenic transcription factors (TFs) required for adipose tissue development. They control the induction of many adipocyte genes and the early phase of adipogenesis in the embryonic development of adipose tissue. Adipose tissue continues to expand after birth, which, as a late phase of adipogenesis, requires the lipogenesis of adipocytes. In particular, the liver and adipose tissues are major sites for de novo lipogenesis (DNL), where carbohydrates are primarily converted to fatty acids. Furthermore, fatty acids are esterified with glycerol-3-phosphate to produce triglyceride, a major source of lipid droplets in adipocytes. Hepatic DNL has been actively studied, but the DNL of adipocytes in vivo remains not fully understood. Thus, an understanding of lipogenesis and adipose expansion may provide therapeutic opportunities for obesity, type 2 diabetes, and metabolic diseases. In adipocytes, DNL gene expression is transcriptionally regulated by lipogenesis coactivators, as well as by lipogenic TFs such as ChREBP and SREBP1a. Recent in vivo studies have revealed new insights into the lipogenesis gene expression and adipose expansion. Future detailed molecular mechanism studies will determine how nutrients and metabolism regulate DNL and adipose expansion. This review will summarize recent updates of DNL in adipocytes and adipose expansion in terms of transcriptional regulation. PPARγ와 C/EBPα는 adipose tissue 발생에 필요한 핵심 adipogenic TFs이다. 두 TFs는 adipose tissue의 배아 발생에 있어 초기 adipogenesis와 adipocytes 유전자 발현을 조절한다. Adipose expansion은 adipose tissue가 태어난 뒤에도 계속 팽창이 지속되는 것을 말한다. 이러한 adipose expansion은 후기 adipogenesis의 과정인 lipogenesis가 요구된다. 특히 간과 adipose tissue은 탄수화물이 기본적으로 fatty acids으로 전환되는 de novo lipogenesis (DNL)의 주요 장기이다. Fatty acids는 이어서 glycerol-3-phosphate에 에스테르화되어 adipocytes의 lipid droplets 생성을 위해 triglycerides로 전환된다. 간의 DNL이 활발하게 연구가 된 반면, in vivo에서 adipocytes의 DNL은 아직 잘 알려져 있지 않다. 그러므로, adipose expansion과 DNL에 대한 이해는 비만, 2형 당뇨 그리고 대사성 질환을 위한 치료제 개발에 도움을 줄 수 있다. Adipocytes에서 DNL 유전자 발현은 ChREBP나 SREBP1a와 같은 lipogenic TFs 뿐 아니라, lipogenesis coactivator에 의해 전사 수준에서 조절된다. 최근 in vivo 연구에 의해 lipogenesis 유전자 발현과 adipose expansion의 새로운 측면이 밝혀졌다. 향후 구체적인 분자기전 연구는 어떻게 영양분이 DNL과 adipose expansion을 조절하는 지를 규명해 줄 것이다. 본 리뷰논문은 전사조절 관점에서 adipocytes와 adipose expansion에 있어 DNL에 대한 최신 연구결과를 요약정리 할 것이다.

Effect of Thyroid hormone on Lipogenesis in Rat White and Brown Adipocytes Culture System

Kim, Yangha -Moon The Korean Society of Food Science and Nutrition 1998 Preventive Nutrition and Food Science Vol.3 No.4

Thyroid hormone(T3) stimulates hepatic lipogenesis by increasing expression of genes, indluding acetyl-CoA carboxylase and fatty acid synthase. S14 protein, which is thougth to be involved in lipid metabolism , appears to respond in parallel . Effect of T3 on lipogenesis in white and brown adipose tissue are less clear, and may be complicated by indirect effects of the hormone. We developed an adipocytes system where the indirect effects of thyroid hormone are abolished and direct effects of T3 on lipogenesis could be tested. Fat accumulation was mesured by Oil-Red O staining. Insulin clearly enhanced fat accumulation by 2-fold . Isobutylemethylxanthie(IBMX) apeared to inhibit insulin -stimulated fat accumulation. Dexamethasone increased insulin-stimulatedfat accumulation about 1.3-fold. confluent adipocytes were cultured in serum-free medium or medium containing 10% fetal calf serum or 10% fetal calf serum stripped of thyroid hormone and lipogenesis, assessed by the incorporation of 3H2O , was measured. Medium without serum or supplemented with T3-depleted serum did not amplify the stimulatory effect of T3 on lipogenesis compared to medium containing 10% fetal calf seru. Dexamethasone alone led to a decrease inlopogenesis of about 50 % in white adipocytes and 25% in brown adipocytes. However, dexamethasone amplified the lipogenic respnse to T3 by about 30% in whit eadipocytes and 60% in brown adipocytes. T3(1$\mu$M) stimulated lipogenesis and acetyl-CoA carboxylase and fatty acid syntase mRNA levels up to 2 -fold in both types of adipocytes. It seems that these adipocytes systems are as useful model to study the effects of hormones on lipogenic gene expression as well as lipogenesis.

Cloning of porcine chemerin, ChemR23 and GPR1 and their involvement in regulation of Lipogenesis

( Jianfeng Huang ),( Jian Zhang ),( Ting Lei ),( Xiaodong Chen ),( Yan Zhang ),( Lulu Zhou ),( An Yu ),( Zhilong Chen ),( Ronghua Zhou ),( Zaiqing Yang ) 생화학분자생물학회 (구 한국생화학분자생물학회) 2010 BMB Reports Vol.43 No.7

Chemerin is a novel adipokine which is abundant in adipose tissue to promote adipocyte differentiation and with significant relativity to BMI and insulin sensitivity. We report here the molecular characterization of porcine chemerin and its receptors ChemR23 and GPR1, as well as their transcriptional regulation during lipogenesis. Chemerin was mainly expressed in liver, intestine, kidney and adipose tissue, consistent with the expression pattern of GPR1, but not ChemR23, which was predominantly present in spleen and temperately in adipose tissue. We further investigated the lipogenesis-related transcriptional activation of PPARγ and KLF15 on chemerin and its receptors. The data showed that KLF15, but not PPARγ, can up-regulate the mRNA level of chemerin, ChemR23 and GPR1, which was consistent with the results of luciferase assay that confirmed the effect of KLF15 on ChemR23 promoter. Taken together, our data provide basic molecular information for the further investigation on the function of chemerin in lipogenesis. [BMB reports 2010; 43(7): 491-498]

식이 제한이 흰쥐 지방조직의 Lipoprotein Lipase활성과 지방합성에 미치는 영향

이재준 ( Lee Jae Jun ),최미숙 ( Choe Mi Sug ),정정수 ( Jeong Jeong Su ),최병대 ( Choe Byeong Dae ) 한국운동영양학회 2003 Physical Activity and Nutrition (Phys Act Nutr) Vol.7 No.2

The current study was undertaken the effects of various degrees of food restriction on rat adipose tissue lipoprotein lipase (LPL) activity and lipogenesis. Thirty male Sprague-Dawely rats weighing 290 g were divided nto three groups according to body weight and raised for four weeks. The full-fed group was fed ad-libitum and the food restricted groups were fed either mildly restricted (20% food restricted group) or severly restricted diet (40% food restricted group). Lipogenesis was determined by the amount of glucose converted to a total lipid. Serum lipoprotein pattern, triglyceride coneentration and their correlation with LPL activity were also investigated. As expected, body weight gain and epididymal adipose tissue weight were higher in the full-fed group (p<0.05). The serum total cholesterol and LDL cholesterol concentrations were not significantly affected by food restriction. However, HDL-cholesterol concentration and HDL-C/T-C ratio were signiticantly higher in the food restricted groups than they were in the full-fed group (p<0.05). The serum triglyceride concentration of full-fed rats tended to be higher than that of the 40% food restricted rats (p<0.05). There was no difference in lipogenesis between food restricted groups, but lipogenesis was significantly higher in the 40% food restricted group than in the full-fed group (p<0.05). The LPL activity of adipose tissue was significantly lower in the 40% restricted group than that in the full-fed group (p<0.05), but that of the 20% restricted group was similar to the full-fed group. LPL activity in adipose tissue had a positive correlation with triglyceride concentration, which had a negative correlation with HDL-cholesterol concentration. These results suggest that food restriction leads to the decreased activity of LPL, thereby potentially reducing lipid storage.

Estrogen-related receptor γ controls sterol regulatory element-binding protein-1c expression and alcoholic fatty liver

Kim, Don-Kyu,Kim, Yong-Hoon,Lee, Jae-Ho,Jung, Yoon Seok,Kim, Jina,Feng, Rilu,Jeon, Tae-Il,Lee, In-Kyu,Cho, Sung Jin,Im, Seung-Soon,Dooley, Steven,Osborne, Timothy F.,Lee, Chul-Ho,Choi, Hueng-Sik Elsevier 2019 Biochimica et biophysica acta, Molecular and cell Vol.1864 No.12

<P><B>Abstract</B></P> <P>Although SREBP-1c regulates key enzymes required for hepatic <I>de novo</I> lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB<SUB>1</SUB> receptor signaling. Deletion and mutation analyses of the <I>Srebp-1c</I> gene promoter showed that ERRγ directly regulates <I>Srebp-1c</I> gene transcription <I>via</I> binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in <I>Srebp-1c</I>-knockout hepatocytes. Conversely, liver-specific ablation of <I>ERRγ</I> gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ERRγ is induced by alcohol-mediated activation of CB<SUB>1</SUB> receptor signaling. </LI> <LI> ERRγ increases hepatic SREBP-1c expression and alcohol-mediated hepatic lipogenesis </LI> <LI> An ERRγ inverse agonist inhibits SREBP-1c-induced hepatic <I>de novo</I> lipogenesis. </LI> <LI> An ERRγ inverse agonist ameliorates alcohol fatty liver disease. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

마황천오 약침액이 3T3-L1 지방세포 분화 및 유전자발현에 미치는 영향

강경화 ( Kyung Hwa Kang ) 경락경혈학회 2014 Korean Journal of Acupuncture Vol.31 No.4

Objectives : Mahuang-Chuanwu(Mahwang-Cheonoh) Pharmacopuncture(MCP) has been used to treat obesity in Clinical Korean Medicine. MCP solution(MCPS) is also expected to have strong anti-obesity activities. However, little is known about the mechanisms of its inhibitory effects on adipocyte differentiation and lipogenesis. Methods : In the present study, we examined the effects of MCPS on differentiation and lipogenesis of 3T3-L1 adipocytes. To elucidate the mechanism of the effects of MCPS on lowering lipid content in 3T3-L1 adipocytes, we examined whether MCPS modulates the expressions of transcription factors to induce lipogenesis and adipogenic genes related to regulate the accumulation of lipids. Results : Our results showed that MCPS significantly inhibited differentiation and lipogenesis of 3T3-L1 adipocytes in a dose-dependent manner. MCPS suppressed the mRNA expressions of cytidine-cytidine-adenosine-adenosine-thymidine(CCAAT)/enhancer binding proteins α(C/EBPα), C/EBP β, C/EBPδ, and peroxisome proliferator-activated receptor γ(PPARγ) genes related to the induction of adipose differentiation. MCPS inhibited the mRNA expressions of adipose-specific aP2, adipsin, lipoprotein lipase(LPL), CD36, TGF-β, and leptin genes related to the fat formation. MCPS downregulated the mRNA expressions of liver X receptor(LXR) α and fatty acid synthase(FAS) genes related to the induction of lipogenesis. In addition, MCPS reduced the production of adipocyte-induced pro-inflammatory cytokines. Conclusions : MCPS could regulate the accumulation of lipids and expression of adipogenic genes via inhibition of transcript factors related to induction of adipose differentiation.

Hypotriglyceridemic effects of brown seaweed consumption via regulation of bile acid excretion and hepatic lipogenesis in high fat diet-induced obese mice

A-Reum Han,Jae-Hoon Kim,Eunyoung Kim,Jiamei Cui,In-Suk Chai,Guiguo Zhang,Yunkyoung Lee 한국영양학회 2020 Nutrition Research and Practice Vol.14 No.6

BACKGROUND/OBJECTIVES: The present study aimed to further investigate the potential health beneficial effects of long-term seaweed supplementation on lipid metabolism and hepatic functions in DIO mice. MATERIALS/METHODS: Four brown seaweeds (Undaria pinnatifida [UP], Laminaria japonica [LJ], Sargassum fulvellum [SF], or Hizikia fusiforme [HF]) were added to a high fat diet (HFD) at a 5% ratio and supplemented to C57BL/6N mice for 16 weeks. Triglycerides (TGs) and total cholesterol (TC) in the liver, feces, and plasma were measured. Fecal bile acid (BA) levels in feces were monitored. Hepatic insulin signaling- and lipogenesis-related proteins were evaluated by Western blot analysis. RESULTS: Fasting blood glucose levels were significantly reduced in the LJ, SF, and HF groups compared to the HFD group by the end of 16-week feeding period. Plasma TG levels and hepatic lipid accumulation were significantly reduced in all 4 seaweed supplemented groups, whereas plasma TC levels were only suppressed in the UP and HF groups compared to the HFD group. Fecal BA levels were significantly elevated by UP, LJ, and SF supplementation compared to HFD feeding only. Lastly, regarding hepatic insulin signaling-related proteins, phosphorylation of 5′-AMP-activated protein kinase was significantly up-regulated by all 4 types of seaweed, whereas phosphorylation of protein kinase B was up-regulated only in the SF and HF groups. Lipogenesis-related proteins in the liver were effectively down-regulated by HF supplementation in DIO mice. CONCLUSIONS: Brown seaweed consumption showed hypotriglyceridemic effects in the prolonged DIO mouse model. Specifically, combinatory regulation of BA excretion and lipogenesis-related proteins in the liver by seaweed supplementation contributed to the reduction of plasma and hepatic TG levels, which inhibited hyperglycemia in DIO mice. Thus, the discrepant and species-specific functions of brown seaweeds provide novel insights for the selection of future targets for therapeutic agents.

Dansameum regulates hepatic lipogenesis and inflammation in vitro and in vivo

안상현,이강파,김기봉,최준용,박선영,천진홍 한국식품과학회 2019 Food Science and Biotechnology Vol.28 No.5

Although the clinical guidelines for nonalcoholic fatty liver disease (NAFLD) therapy recommended hepato-protection and exercise to reduce body weight, no established medication exists for NAFLD treatment. Thus, the effect of a candidate substance, dansameum (DSE), using an in vitro and NAFLD mouse model (that is, apolipoprotein E-Knockout mice), were investigated. The molecular pathways for lipogenesis and inflammation were evaluated using Nile staining, Western blotting, reverse transcription-polymerase chain reaction, and immunohistochemistry. It was shown that DSE significantly ameliorated the production of lipogenesis-related factors, including liver X receptor-α, peroxisome proliferator-activated receptor-γ, sterol regulatory element binding protein-1, fatty acid synthase, acetyl-CoA carboxylase 1, and CD36. In addition, DSE significantly reduced the production of inflammation factors, including interleukin-1β, interleukin-6, and nuclear factor kappa B. Furthermore, DSE significantly reduced the phosphorylation of c-Jun amino terminal kinase. Taken together, this suggests that DSE may be a functional food candidate for regulating NAFLD, based on its effects.

순무(Brassica rapa L.)와 월동무(Raphanus sativus L.)의 PI3K/AKT 조절을 통한 Adipogenesis 및 Lipogenesis 억제 효과

황혜정(Hye-Jeong Hwang),박나영(NaYeong Park),황인국(In Guk Hwang),강해주(Hae Ju Kang),방경원(Kyeong Won Bang),황경아(Kyung-A Hwang) 한국식품영양과학회 2022 한국식품영양과학회지 Vol.51 No.10

본 연구에서는 순무(RG)와 월동무(RJ)의 항비만 효과를 확인하고자 MDI로 분화를 유도한 C3H10T1/2 세포에서 지질 축적 및 지방합성 억제 효과를 평가하였다. 무 추출물을 처리한 지방분화 세포의 지질 축적 정도와 triglyceride 함량을 측정한 결과, 무 추출물에 의해 지방구 형성과 triglyceride 축적을 감소시켰고, 특히 RJ 1,000 μg/mL 처리 시 높은 억제 효과를 보였다. 또한, 지방분화를 통해 지방구 형성(adipogenesis)에 관여하는 전사인자(C/EBPα와 β, PPARγ, SREBP-1c)와 지방합성(lipogenesis)에 관여하는 인자(aP2, FAS, SCD1)의 발현량을 측정한 결과, 시료 처리 농도 의존적으로 유전자와 단백질 발현량이 감소한 것을 확인하였으며, 모든 인자에서 RG 처리군보다 RJ 처리군의 효능이 더욱 우수하였다. 또한, MDI 처리 대조군에서 분비가 증가한 leptin과 adiponectin의 생성량이 무 추출물 처리에 의해 농도 의존적으로 감소하는 결과를 확인하였으며, 이러한 결과는 세포 표면 leptin 수용체에 leptin 결합에 의해 활성화되는 PI3K/AKT 신호 관련 인자들의 유전자 발현이 무 추출물 처리에 의해 억제됨으로써 지방 합성 및 지질 축적을 억제하여 무 추출물이 비만 개선에 효과적임을 밝혀냈다. 이상의 결과로부터 RG와 RJ가 지방세포 분화 기전과 지방분화 호르몬의 생성량을 억제함으로써 지방분화 및 합성 억제 효능이 우수함을 확인하였다. 향후 전임상 효능 평가와 RG와 RJ가 함유한 기능성 성분 연구가 이루어진다면 체지방감소에 도움을 주는 건강기능식품 소재로서의 활용 가능성을 제시할 수 있을 것으로 생각된다. Radish (Raphanus sativus L.) is a representative root vegetable widely cultivated in Asia and known to have various physiological effects, such as gastric protective, anti-inflammatory, antioxidant, and hemostasis improving effects, and to ameliorate digestive disorders. However, studies on the antiobesity effects of white and red radish are inadequate. Therefore, in this study, the anti-adipogenic and anti-lipogenic effects of Ganghwa (RG) and Jeju (RJ) radishes were investigated in C3H10T1/2 cells. Lipid accumulation inhibition by Oil Red O staining and TG contents confirmed that at 1,000 μg/mL RG and RJ significantly inhibited lipid accumulation and dose-dependently reduced the mRNA and protein levels of major adipogenesis and lipogenesis-related factors. In addition, inhibition of the expression of genes in the PI3K/Akt pathway by RG or RJ markedly increased leptin and adiponectin levels. These results indicate radishes are potential functional materials that inhibit adipocyte differentiation and lipid accumulation.