Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance

Shamma Almuraikhy; Wael Kafienah; Moataz Bashah; Ilhame Diboun; Morana Jaganjac; Fatima Al-Khelaifi; Houari Abdesselem; Nayef A. Mazloum; Mohammed Alsayrafi; Vidya Mohamed-Ali; Mohamed A. Elrayess

doi:10.1007/s00125-016-4031-3

Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance

Shamma Almuraikhy, Wael Kafienah, Moataz Bashah, Ilhame Diboun, Morana Jaganjac, Fatima Al-Khelaifi, Houari Abdesselem, Nayef A. Mazloum, Mohammed Alsayrafi, Vidya Mohamed-Ali, Mohamed A. Elrayess^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

72 Citations (Scopus)

Abstract

Aims/hypothesis: A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. Methods: Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. Results: Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. Conclusions/interpretation: Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.

Original language	English
Pages (from-to)	2406-2416
Number of pages	11
Journal	Diabetologia
Volume	59
Issue number	11
DOIs	https://doi.org/10.1007/s00125-016-4031-3
Publication status	Published - 1 Nov 2016
Externally published	Yes

Keywords

Adipogenesis
Insulin resistance
Insulin sensitivity
Interleukin-6
Obesity
Subcutaneous fat
Type 2 diabetes mellitus

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10.1007/s00125-016-4031-3

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title = "Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance",

abstract = "Aims/hypothesis: A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. Methods: Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. Results: Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. Conclusions/interpretation: Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.",

keywords = "Adipogenesis, Insulin resistance, Insulin sensitivity, Interleukin-6, Obesity, Subcutaneous fat, Type 2 diabetes mellitus",

author = "Shamma Almuraikhy and Wael Kafienah and Moataz Bashah and Ilhame Diboun and Morana Jaganjac and Fatima Al-Khelaifi and Houari Abdesselem and Mazloum, {Nayef A.} and Mohammed Alsayrafi and Vidya Mohamed-Ali and Elrayess, {Mohamed A.}",

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doi = "10.1007/s00125-016-4031-3",

language = "English",

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AU - Almuraikhy, Shamma

AU - Kafienah, Wael

AU - Bashah, Moataz

AU - Diboun, Ilhame

AU - Jaganjac, Morana

AU - Al-Khelaifi, Fatima

AU - Abdesselem, Houari

AU - Mazloum, Nayef A.

AU - Alsayrafi, Mohammed

AU - Mohamed-Ali, Vidya

AU - Elrayess, Mohamed A.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Aims/hypothesis: A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. Methods: Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. Results: Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. Conclusions/interpretation: Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.

AB - Aims/hypothesis: A subset of obese individuals remains insulin sensitive by mechanisms as yet unclear. The hypothesis that maintenance of normal subcutaneous (SC) adipogenesis accounts, at least partially, for this protective phenotype and whether it can be abrogated by chronic exposure to IL-6 was investigated. Methods: Adipose tissue biopsies were collected from insulin-sensitive (IS) and insulin-resistant (IR) individuals undergoing weight-reduction surgery. Adipocyte size, pre-adipocyte proportion of stromal vascular fraction (SVF)-derived cells, adipogenic capacity and gene expression profiles of isolated pre-adipocytes were determined, along with local in vitro IL-6 secretion. Adipogenic capacity was further assessed in response to exogenous IL-6 application. Results: Despite being equally obese, IR individuals had significantly lower plasma leptin and adiponectin levels and higher IL-6 levels compared with age-matched IS counterparts. Elevated systemic IL-6 in IR individuals was associated with hyperplasia of adipose tissue-derived SVF cells, despite higher frequency of hypertrophied adipocytes. SC pre-adipocytes from these tissues exhibited lower adipogenic capacity accompanied by downregulation of PPARγ (also known as PPARG) and CEBPα (also known as CEBPA) and upregulation of GATA3 expression. Impaired adipogenesis in IR individuals was further associated with increased adipose secretion of IL-6. Treatment of IS-derived SC pre-adipocytes with IL-6 reduced their adipogenic capacity to levels of the IR group. Conclusions/interpretation: Obesity-associated insulin resistance is marked by impaired SC adipogenesis, mediated, at least in a subset of individuals, by elevated local levels of IL-6. Understanding the molecular mechanisms underlying reduced adipogenic capacity in IR individuals could help target appropriate therapeutic strategies aimed at those at greatest risk of insulin resistance and type 2 diabetes mellitus.

KW - Adipogenesis

KW - Insulin resistance

KW - Insulin sensitivity

KW - Interleukin-6

KW - Obesity

KW - Subcutaneous fat

KW - Type 2 diabetes mellitus

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JO - Diabetologia

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ER -

Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance

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