SMIM1 absence is associated with reduced energy expenditure and excess weight
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.
Methods
We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1−/− individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.
Findings
We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.
Conclusion
This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.
Funding
This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.
Methods
We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1−/− individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.
Findings
We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.
Conclusion
This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.
Funding
This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
Date Issued
2024-09-13
Date Acceptance
2024-05-29
Citation
Med, 2024, 5 (9), pp.1083-1095.e6
ISSN
2666-6340
Publisher
Cell Press
Start Page
1083
End Page
1095.e6
Journal / Book Title
Med
Volume
5
Issue
9
Copyright Statement
© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38906141
PII: S2666-6340(24)00219-8
Subjects
ADIPONECTIN
BIOBANK
BLOOD-GROUP
DATA QUALITY
DESIGN
LEPTIN
Life Sciences & Biomedicine
Medicine, Research & Experimental
OBESITY
RATIO
Research & Experimental Medicine
RESOURCE
SAFETY
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-06-20