ESPEYB16 11 Obesity and Weight Regulation New Insights into Body Weight Regulation (4 abstracts)
11.3. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
Yang Y , van der Klaauw AA , Zhu L , Cacciottolo TM , He Y , Stadler LKJ , Wang C , Xu P , Saito K , Hinton A Jr. , Yan X , Keogh JM , Henning E , Banton MC , Hendricks AE , Bochukova EG , Mistry V , Lawler KL , Liao L , Xu J , O’Rahilly S , Tong Q , UK10K Consortium , Barroso I , O’Malley BW , Farooqi IS & Xu Y
Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plazam, Houston, TX, USA. yongx@bcm.edu
To read the full abstract: Nat Comm 2019; 10(1): 1718
Steroid receptor coactivator (SRC)-1 mediates nuclear hormone receptors and transcription factor-dependent transcription (1), and interacts with STAT3 (2) an important mediator of leptin-induced POMC expression and hence satiety (3). Src-1 knockout mice are obese (4), however, the underlying mechanism is unclear. In a compelling line of evidence, these authors suggest that SRC-1 deficiency might impair leptin action via reduced STAT3 activation. They show that SRC-1 deficient mice have lower leptin-stimulated pSTAT3 binding to Pomc promoters and lower Pomc mRNA, become more obese on high fat diets and are resistant to the anorectic effect of leptin. In addition, 14 of 15 rare SRC−1 variants found in individuals with severe, early-onset obesity showed reduced SRC-1-STAT3 interaction, reduced POMC-neuron activation, and reduced POMC expression in in-vitro models; only 4 rare variants were identified in normal weight controls.
Extreme obesity, especially with an early onset is highly suspicious of monogenic obesity (5), but underlying genetic causes are found in fewer than 10% of cases (6) implying that there are many yet unknown genetic causes. The finding of a new obesity gene is of high interest as knowing the diagnosis helps to lessen the disease burden for most patients and might also open up future therapeutic strategies both for the affected patients and possibly also for patients with common obesity.
The strength of the study lies in the wide variety of methods used to examine SRC-1 function and the huge cohort of patients studied by DNA sequencing. Limitations include the fact that SRC-1 deficient mice showed only a modest obesity. This is in line with the moderating function of SRC-1, but it raises the question if heterozygous variants in this gene can truly explain the extreme obesity seen in probands (mean BMI z-score =3; age of onset < 10 years). The authors provide no co-segregation analysis to strengthen their case, thus further studies will be needed to prove if variants in SRC-1 truly cause severe obesity.
References: 1. York B, O’Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. Journal of Biological Chemistry. 2010;285(50):38743–50.
2. Giraud S, Bienvenu F, Avril S, Gascan H, Heery DM, Coqueret O. Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. Journal of Biological Chemistry. 2002;277(10):8004–11.
3. Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology. 2007;148(1):72–80.
4. Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O’Malley BW, et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002;111(7):931–41.
5. Kohlsdorf K, Nunziata A, Funcke JB, Brandt S, von Schnurbein J, Vollbach H, et al. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency. International Journal of Obesity (2005). 2018;42(9):1602–9.
6. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. Journal of Medical Genetics. 2018;55(9):578–86.
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ESPE Yearbook of Paediatric Endocrinology
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