OR15-5 The Role of Notch in Adipogenesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR15-Adipokine Action
Basic/Clinical
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 303 (Moscone Center)
David P Sparling*1, Utpal Pajvani1, Sharon E Oberfield2 and Domenico Accili1
1Columbia University, New York, NY, 2Columbia University Medical Center, New York, NY
Different adipose tissue depots display strikingly different pathophysiological properties, some of which may regulate metabolism and underlie the predisposition to obesity. While increased visceral adipose tissue (VAT) predisposes to insulin resistance, increased subcutaneous adipose tissue (SCAT) may not; furthermore, higher brown adipose tissue (BAT) mass protects against diet-induced obesity (1). We have recently shown that Notch, classically associated with cell-fate decisions, also plays a role in control of metabolism in interactions with the insulin-regulated transcription factor FoxO1 (2). We hypothesized that Notch signaling is present and differentially regulated in developed adipose depots. We also predicted that Notch signaling might correlate with classic adipose depot markers, and thus identify adipocyte lineage.

Notch and FoxO1 coordinate metabolism and differentiation in a variety of cell types, and genetic/pharmacologic blockade of Notch signaling increases insulin sensitivity (2). FoxO1 gain-of-function blocks differentiation of both adipocyte and myocyte cell lines, which can be rescued by inhibition of Notch in myocytes (3, 4). Notch1 regulates expression of adipogenic transcription factors in vitro, and down-regulation of Notch1 prevents adipocyte differentiation (5). Confusingly, Notch activation by Jagged1, or constitutive expression of Notch target Hes1, prevents differentiation of 3T3-L1 preadipoctyes (6). No study as yet has addressed the potential role of Notch signaling in adipocyte-type specification, or the presence and regulation of Notch signaling in vivo.

Using qRT-PCR, we examined transcription of components of the Notch cascade in BAT, SCAT and VAT in control v. cold-exposed mice, a model of brown adipogenesis. We show that Notch target Hes1 is repressed by 50% in VAT but induced 5.5-fold in BAT following cold exposure (n=6/condition, p<0.05). Notch receptors and ligands are also variably regulated in response to cold exposure (p<0.05). Notch target expression in VAT also appears to be affected in multiple metabolic conditions.

These data indicate that Notch signaling is active in vivo and is regulated in an adipose-depot specific manner, possibly participating in adipocyte lineage. To investigate in greater detail, we have developed mice with adipose-specific knockout of components of Notch signaling, and will present data that further characterize the role of Notch in adipogenesis.

1) Cinti S. Ann Med. 2011 Mar; 43(2): 104-15.  2) Pajvani UB, et al. Nat Med. 2011 Jul 31; 17(8): 961-7. 3) Kitamura T, et al. J Clin Invest. 2007 Sep; 117(9): 2477-85. 4) Nakae J, et al. Dev Cell. 2003 Jan; 4(1): 119-29.5) Garces C, et al. J Biol Chem. 1997 Nov 21; 272(47): 29729-34.  6) Ross DA, et al. Mol Cell Biol. 2004 Apr; 24(8): 3505-13.

Nothing to Disclose: DPS, UP, SEO, DA

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