TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
Introduction Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2022
|
| _version_ | 1826307850999169024 |
|---|---|
| author | Verma, M Loh, N Sabaratnam, R Vasan, S Van Dam, A Todorčević, M Neville, M Toledo, E Karpe, F Christodoulides, C |
| author_facet | Verma, M Loh, N Sabaratnam, R Vasan, S Van Dam, A Todorčević, M Neville, M Toledo, E Karpe, F Christodoulides, C |
| author_sort | Verma, M |
| collection | OXFORD |
| description | Introduction
Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism.
Objective
To map the expression of TCF7L2 in human AT, examine its role in human adipose cell biology in vitro, and investigate the effects of the fine-mapped T2D-risk allele at rs7903146 on AT morphology and TCF7L2 expression.
Methods
Ex vivo gene expression studies of TCF7L2 in whole and fractionated human AT. In vitro TCF7L2 gain- and/or loss-of-function studies in primary and immortalized human adipose progenitor cells (APCs) and mature adipocytes (mADs). AT phenotyping of rs7903146 T2D-risk variant carriers and matched controls.
Results
Adipose progenitors (APs) exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in whole subcutaneous abdominal AT but paradoxically increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in abdominal APs led to dose-dependent activation of WNT/β-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, near-total KD impaired lipid accumulation and adipogenic gene expression. Over-expression of TCF7L2 accelerated adipogenesis. In contrast, TCF7L2-KD in gluteal APs dose-dependently enhanced lipid accumulation. Transcriptome-wide profiling revealed that TCF7L2 might modulate multiple aspects of AP biology including extracellular matrix secretion, immune signaling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity.
Conclusions
TCF7L2 plays a complex role in AP biology and has both dose- and depot-dependent effects on adipogenesis. In addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 might also influence T2D risk by modulating AP function.
|
| first_indexed | 2024-03-07T07:10:50Z |
| format | Journal article |
| id | oxford-uuid:71ae6e5c-7483-4d69-8cac-ed1b445a84f9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:10:50Z |
| publishDate | 2022 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:71ae6e5c-7483-4d69-8cac-ed1b445a84f92022-06-16T12:54:02ZTCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:71ae6e5c-7483-4d69-8cac-ed1b445a84f9EnglishSymplectic ElementsElsevier2022Verma, MLoh, NSabaratnam, RVasan, SVan Dam, ATodorčević, MNeville, MToledo, EKarpe, FChristodoulides, CIntroduction Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism. Objective To map the expression of TCF7L2 in human AT, examine its role in human adipose cell biology in vitro, and investigate the effects of the fine-mapped T2D-risk allele at rs7903146 on AT morphology and TCF7L2 expression. Methods Ex vivo gene expression studies of TCF7L2 in whole and fractionated human AT. In vitro TCF7L2 gain- and/or loss-of-function studies in primary and immortalized human adipose progenitor cells (APCs) and mature adipocytes (mADs). AT phenotyping of rs7903146 T2D-risk variant carriers and matched controls. Results Adipose progenitors (APs) exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in whole subcutaneous abdominal AT but paradoxically increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in abdominal APs led to dose-dependent activation of WNT/β-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, near-total KD impaired lipid accumulation and adipogenic gene expression. Over-expression of TCF7L2 accelerated adipogenesis. In contrast, TCF7L2-KD in gluteal APs dose-dependently enhanced lipid accumulation. Transcriptome-wide profiling revealed that TCF7L2 might modulate multiple aspects of AP biology including extracellular matrix secretion, immune signaling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity. Conclusions TCF7L2 plays a complex role in AP biology and has both dose- and depot-dependent effects on adipogenesis. In addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 might also influence T2D risk by modulating AP function. |
| spellingShingle | Verma, M Loh, N Sabaratnam, R Vasan, S Van Dam, A Todorčević, M Neville, M Toledo, E Karpe, F Christodoulides, C TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes |
| title | TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
|
| title_full | TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
|
| title_fullStr | TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
|
| title_full_unstemmed | TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
|
| title_short | TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes
|
| title_sort | tcf7l2 plays a complex role in human adipose progenitor biology which might contribute to genetic susceptibility to type 2 diabetes |
| work_keys_str_mv | AT vermam tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT lohn tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT sabaratnamr tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT vasans tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT vandama tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT todorcevicm tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT nevillem tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT toledoe tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT karpef tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes AT christodoulidesc tcf7l2playsacomplexroleinhumanadiposeprogenitorbiologywhichmightcontributetogeneticsusceptibilitytotype2diabetes |