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Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants.
PLoS One 2014; 9(4):e93629Plos

Abstract

BACKGROUND

The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals. Though some rare variants in MC4R discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects.

SUBJECTS/METHODS

In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of MC4R. We matched rare variant carriers to patients with the MC4R reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. In vitro, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy.

RESULTS

While carrying a rare MC4R allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, V95I, I137T or L250Q, lost less weight after surgery. In vitro, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between in vitro signaling and pre- or post-surgery clinical phenotype.

CONCLUSIONS

These data suggest that subtle differences in receptor signaling conferred by rare MC4R variants combined with additional factors predispose carriers to obesity. In the absence of complete MC4R deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention.

Authors+Show Affiliations

Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Geisinger Obesity Institute, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America.Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, United States of America; Geisinger Obesity Institute, Geisinger Clinic, Danville, Pennsylvania, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24705671

Citation

Moore, Bryn S., et al. "Long-term Weight-loss in Gastric Bypass Patients Carrying Melanocortin 4 Receptor Variants." PloS One, vol. 9, no. 4, 2014, pp. e93629.
Moore BS, Mirshahi UL, Yost EA, et al. Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. PLoS ONE. 2014;9(4):e93629.
Moore, B. S., Mirshahi, U. L., Yost, E. A., Stepanchick, A. N., Bedrin, M. D., Styer, A. M., ... Mirshahi, T. (2014). Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. PloS One, 9(4), pp. e93629. doi:10.1371/journal.pone.0093629.
Moore BS, et al. Long-term Weight-loss in Gastric Bypass Patients Carrying Melanocortin 4 Receptor Variants. PLoS ONE. 2014;9(4):e93629. PubMed PMID: 24705671.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. AU - Moore,Bryn S, AU - Mirshahi,Uyenlinh L, AU - Yost,Evan A, AU - Stepanchick,Ann N, AU - Bedrin,Michael D, AU - Styer,Amanda M, AU - Jackson,Kathryn K, AU - Still,Christopher D, AU - Breitwieser,Gerda E, AU - Gerhard,Glenn S, AU - Carey,David J, AU - Mirshahi,Tooraj, Y1 - 2014/04/04/ PY - 2013/12/18/received PY - 2014/02/06/accepted PY - 2014/4/8/entrez PY - 2014/4/8/pubmed PY - 2015/6/16/medline SP - e93629 EP - e93629 JF - PloS one JO - PLoS ONE VL - 9 IS - 4 N2 - BACKGROUND: The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals. Though some rare variants in MC4R discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects. SUBJECTS/METHODS: In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of MC4R. We matched rare variant carriers to patients with the MC4R reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. In vitro, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy. RESULTS: While carrying a rare MC4R allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, V95I, I137T or L250Q, lost less weight after surgery. In vitro, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between in vitro signaling and pre- or post-surgery clinical phenotype. CONCLUSIONS: These data suggest that subtle differences in receptor signaling conferred by rare MC4R variants combined with additional factors predispose carriers to obesity. In the absence of complete MC4R deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24705671/Long_term_weight_loss_in_gastric_bypass_patients_carrying_melanocortin_4_receptor_variants_ L2 - http://dx.plos.org/10.1371/journal.pone.0093629 DB - PRIME DP - Unbound Medicine ER -