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Browsing by Author "Pederson, Bartholomew A."
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Item Glycogen Dynamics Drives Lipid Droplet Biogenesis during Brown Adipocyte Differentiation(Cell Press, 2019-11-05) Mayeuf-Louchart, Alicia; Lancel, Steve; Sebti, Yasmine; Pourcet, Benoit; Loyens, Anne; Delhaye, Stéphane; Duhem, Christian; Beauchamp, Justine; Ferri, Lise; Thorel, Quentin; Boulinguiez, Alexis; Zecchin, Mathilde; Dubois-Chevalier, Julie; Eeckhoute, Jérôme; Vaughn, Logan T.; Roach, Peter J.; Dani, Christian; Pederson, Bartholomew A.; Vincent, Stéphane D.; Staels, Bart; Duez, Hélène; Biochemistry and Molecular Biology, School of MedicineBrowning induction or transplantation of brown adipose tissue (BAT) or brown/beige adipocytes derived from progenitor or induced pluripotent stem cells (iPSCs) can represent a powerful strategy to treat metabolic diseases. However, our poor understanding of the mechanisms that govern the differentiation and activation of brown adipocytes limits the development of such therapy. Various genetic factors controlling the differentiation of brown adipocytes have been identified, although most studies have been performed using in vitro cultured pre-adipocytes. We investigate here the differentiation of brown adipocytes from adipose progenitors in the mouse embryo. We demonstrate that the formation of multiple lipid droplets (LDs) is initiated within clusters of glycogen, which is degraded through glycophagy to provide the metabolic substrates essential for de novo lipogenesis and LD formation. Therefore, this study uncovers the role of glycogen in the generation of LDs.Item A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice(PLOS, 2008-01-29) Savage, David B.; Zha, Lanmin; Ravikumar, Balasubramanian; Choi, Cheol Soo; Snaar, Johanna E.; McGuire, Amanda C.; Wou, Sung-Eun; Medina-Gomez, Gemma; Kim, Sheene; Bock, Cheryl B.; Segvich, Dyann M.; Vidal-Puig, Antonio; Wareham, Nicholas J.; Shulman, Gerald I.; Karpe, Fredrik; Taylor, Roy; Pederson, Bartholomew A.; Roach, Peter J.; O’Rahilly, Stephen; DePaoli-Roach, Anna A.; Biochemistry and Molecular Biology, School of MedicineBackground Stored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding RGL, a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant. Methods and Findings In this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo 13C magnetic resonance spectroscopy studies, demonstrate that human carriers (n = 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content. Conclusions Thus, PPP1R3A C1984ΔAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in ∼1 in 70 UK whites increases the potential biomedical relevance of these observations.