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Hall, Jessica

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Hall

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Jessica

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Hall, Jessica
Author's Publications: search.filters.isAuthorOfPublication.35081408-2664-4884-9f13-271ed54111d2

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    Phosphorylation of Beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes
    (Elsevier, 2018) Hong, Shangyu; Song, Wei; Zushin, Peter-James H.; Liu, Bingyang; Jedrychowski, Mark; Mina, Amir I.; Deng, Zhaoming; Cabarkapa, Dimitrije; Hall, Jessica; Palmer, Colin J.; Aliakbarian, Hassan; Szpyt, John; Gygi, Steven; Tavakkoli, Ali; Lynch, Lydia; Perrimon, Norbert; Banks, Alexander
    Objective: The inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity. Methods and Results: We provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the β3-adrenergic receptor (β3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type β3AR exhibited β3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of β3AR was mutated to alanine. Conclusion: Taken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the β3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.
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    Thyroid Hormone and Insulin Metabolic Actions on Energy and Glucose Homeostasis
    (2014-06-06) Hall, Jessica; Puigserver, Pere Puigserver; Maratos-Flier, Eleftheria; Banks, Alexander; Ruderman, Neil
    Faced with an environment of constantly changing nutrient availability, mammals have adapted complex homeostatic mechanisms to maintain energy balance. Deviations from this balance are largely corrected through a concerted, multi-organ effort that integrates hormonal signals with transcriptional regulatory networks. When these relationships are altered, as with over-nutrition and insulin resistance, metabolic disease ensues. Here, I present data concerning two distinct transcriptional pathways--one for thyroid hormone (TH) and one for insulin--that confer hormone responsiveness on metabolic gene programs that preserve energy homeostasis.
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    Disruption of Thyroid Hormone Activation in Type 2 Deiodinase Knockout Mice Causes Obesity With Glucose Intolerance and Liver Steatosis Only at Thermoneutrality
    (American Diabetes Association, 2011) Castillo, Melany; Hall, Jessica; Correa-Medina, Mayrin; Ueta, Cintia; Won Kang, Hye; Cohen, David E.; Bianco, Antonio C.
    Objective: Thyroid hormone accelerates energy expenditure; thus, hypothyroidism is intuitively associated with obesity. However, studies failed to establish such a connection. In brown adipose tissue (BAT), thyroid hormone activation via type 2 deiodinase (D2) is necessary for adaptive thermogenesis, such that mice lacking D2 (D2KO) exhibit an impaired thermogenic response to cold. Here we investigate whether the impaired thermogenesis of D2KO mice increases their susceptibility to obesity when placed on a high-fat diet. Research Design and Methods: To test this, D2KO mice were admitted to a comprehensive monitoring system acclimatized to room temperature (22\(^\circ\)C) or thermoneutrality (30\(^\circ\)C) and kept either on chow or high-fat diet for 60 days. Results: At 22\(^\circ\)C, D2KO mice preferentially oxidize fat, have a similar sensitivity to diet-induced obesity, and are supertolerant to glucose. However, when thermal stress is eliminated at thermoneutrality (30\(^\circ\)C), an opposite phenotype is encountered, one that includes obesity, glucose intolerance, and exacerbated hepatic steatosis. We suggest that a compensatory increase in BAT sympathetic activation of the D2KO mice masks metabolic repercussions that they would otherwise exhibit. Conclusions: Thus, upon minimization of thermal stress, high-fat feeding reveals the defective capacity of D2KO mice for diet-induced thermogenesis, provoking a paradigm shift in the understanding of the role of the thyroid hormone in metabolism.