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  1. Article ; Online: Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration

    Adilson Guilherme / Batuhan Yenilmez / Alexander H. Bedard / Felipe Henriques / Dianxin Liu / Alexandra Lee / Lauren Goldstein / Mark Kelly / Sarah M. Nicoloro / Min Chen / Lee Weinstein / Sheila Collins / Michael P. Czech

    Cell Reports, Vol 31, Iss 5, Pp - (2020)

    2020  

    Abstract: Summary: Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled ... ...

    Abstract Summary: Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.
    Keywords beige adipocytes ; de novo lipogenesis ; sympathetic nerve ; thyroid hormones ; Adrb3 ; mTORC1 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease

    Emmanouela Tsagkaraki / Sarah M. Nicoloro / Tiffany DeSouza / Javier Solivan-Rivera / Anand Desai / Lawrence M. Lifshitz / Yuefei Shen / Mark Kelly / Adilson Guilherme / Felipe Henriques / Nadia Amrani / Raed Ibraheim / Tomas C. Rodriguez / Kevin Luk / Stacy Maitland / Randall H. Friedline / Lauren Tauer / Xiaodi Hu / Jason K. Kim /
    Scot A. Wolfe / Erik J. Sontheimer / Silvia Corvera / Michael P. Czech

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Worldwide pandemics of obesity and diabetes prompt an urgent need for new approaches to their prevention and cure. Here the authors present a CRISPR-based strategy that enhances the therapeutic potential of human adipocytes when implanted in obese mice. ...

    Abstract Worldwide pandemics of obesity and diabetes prompt an urgent need for new approaches to their prevention and cure. Here the authors present a CRISPR-based strategy that enhances the therapeutic potential of human adipocytes when implanted in obese mice.
    Keywords Science ; Q
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice

    Tony Jourdan / Sarah M. Nicoloro / Zhou Zhou / Yuefei Shen / Jie Liu / Nathan J. Coffey / Resat Cinar / Grzegorz Godlewski / Bin Gao / Myriam Aouadi / Michael P. Czech / George Kunos

    Molecular Metabolism, Vol 6, Iss 11, Pp 1517-

    2017  Volume 1528

    Abstract: Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver ... ...

    Abstract Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-α, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. Methods: We used intravenously administered β-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro-inflammatory mechanism.
    Keywords CB1 receptors ; Kupffer cells ; Insulin resistance ; Inflammation ; siRNA ; Internal medicine ; RC31-1245
    Subject code 571
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: A major role of insulin in promoting obesity-associated adipose tissue inflammation

    David J. Pedersen / Adilson Guilherme / Laura V. Danai / Lauren Heyda / Anouch Matevossian / Jessica Cohen / Sarah M. Nicoloro / Juerg Straubhaar / Hye Lim Noh / DaeYoung Jung / Jason K. Kim / Michael P. Czech

    Molecular Metabolism, Vol 4, Iss 7, Pp 507-

    2015  Volume 518

    Abstract: Objective: Adipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of ...

    Abstract Objective: Adipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation. Methods: Circulating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored. Conversely, insulin was infused into lean mice to determine its affects on the above parameters. Results: Lowering circulating insulin levels in obese mice by streptozotocin treatment decreased macrophage content in AT, enhancing insulin stimulated Akt phosphorylation and de novo lipogenesis (DNL). Moreover, responsiveness of blood glucose levels to injected insulin was improved by streptozotocin and diazoxide treatments of obese mice without changes in body weight. Remarkably, even in lean mice, infusion of insulin under constant euglycemic conditions stimulated expression of cytokines in AT. Consistent with these findings, insulin treatment of 3T3-L1 adipocytes caused a 10-fold increase in CCL2 mRNA levels within 6 h, which was blocked by the ERK inhibitor PD98059. Conclusion: Taken together, these results indicate that obesity-associated hyperinsulinemia unexpectedly drives AT inflammation in obese mice, which in turn contributes to factors that suppress insulin-stimulated adipocyte DNL and systemic insulin sensitivity.
    Keywords Obesity ; Hyperinsulinemia ; Adipose tissue ; Inflammation ; Insulin resistance ; Internal medicine ; RC31-1245
    Language English
    Publishing date 2015-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance

    Marina T. DiStefano / Rachel J. Roth Flach / Ozlem Senol-Cosar / Laura V. Danai / Joseph V. Virbasius / Sarah M. Nicoloro / Juerg Straubhaar / Sezin Dagdeviren / Martin Wabitsch / Olga T. Gupta / Jason K. Kim / Michael P. Czech

    Molecular Metabolism, Vol 5, Iss 12, Pp 1149-

    2016  Volume 1161

    Abstract: Objective: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that ... ...

    Abstract Objective: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. Method: White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. Results: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. Conclusions: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers ...
    Keywords Internal medicine ; RC31-1245
    Subject code 616
    Language English
    Publishing date 2016-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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