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Updated: Feb 27, 2026
Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
Independent tissue contributors to obesity-associated insulin resistance
Yvo Ham Kusters1,2,3, Casper G Schalkwijk1,2,3, Alfons Jhm Houben1,2
1Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
Background:
Induction of insulin resistance is a key pathway through which obesity increases risk of type 2 diabetes, hypertension, dyslipidemia, and cardiovascular events. Although the detrimental effects of obesity on insulin sensitivity are incompletely understood, accumulation of visceral, subcutaneous, and liver fat and impairment of insulin-induced muscle microvascular recruitment (MVR) may be involved. As these phenotypic changes often coincide in obesity, we aimed to unravel whether they independently contribute to insulin resistance and thus constitute separate targets for intervention.
Methods:
We measured visceral (VAT) and subcutaneous adipose tissue (SAT) volumes and intrahepatic lipid (IHL) content by MRI, and whole body glucose disposal (WBGD) and MVR (using contrast-enhanced ultrasound) responses to a euglycemic insulin clamp in lean (n = 25) and abdominally obese men (n = 52). Abdominally obese men were randomized to dietary weight loss intervention or habitual diet.
Results:
Obesity-associated increases in VAT, SAT, and IHL, along with the decrease in MVR, contributed independently to insulin resistance. Moreover, a dietary weight loss intervention reduced insulin resistance, and mediation analyses showed that decreased IHL and insulin-induced MVR, but not decreased VAT or SAT volumes, independently contributed to improved insulin resistance seen with weight loss.
Conclusion:
Quantifying the mutually independent contributions of visceral and subcutaneous adipose tissue, intrahepatic lipid, and insulin-induced muscle microvascular recruitment reveals distinct targets for treating obesity-associated insulin resistance.
Trial Registration:
Clinicaltrials.gov NCT01675401.
Funding:
Funding was from the Top Institute Food and Nutrition.
Insights
Obesity increases insulin resistance through visceral fat, liver fat, and reduced muscle microvascular recruitment. Weight loss improves insulin sensitivity by reducing liver fat and improving muscle microvascular recruitment.
Area of Science:
- Metabolic health and obesity research.
- Cardiovascular disease risk factors.
Background:
- Obesity is a major risk factor for type 2 diabetes, hypertension, dyslipidemia, and cardiovascular events, primarily through insulin resistance.
- The precise mechanisms linking obesity to insulin resistance are not fully understood but may involve fat accumulation and impaired muscle microvascular recruitment.
- Visceral, subcutaneous, and liver fat accumulation, along with reduced insulin-induced muscle microvascular recruitment (MVR), are potential contributors to obesity-associated insulin resistance.
Purpose of the Study:
- To determine the independent contributions of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic lipid (IHL) content, and MVR to insulin resistance in abdominally obese men.
- To investigate whether these factors represent distinct targets for intervention in managing obesity-related insulin resistance.
Main Methods:
- Cross-sectional study measuring VAT, SAT, and IHL using MRI, and assessing whole-body glucose disposal (WBGD) and MVR via contrast-enhanced ultrasound during a euglycemic insulin clamp in lean and obese men.
- Randomized controlled trial where obese men were assigned to a dietary weight loss intervention or a control group.
Main Results:
- Obesity was associated with increased VAT, SAT, IHL, and decreased MVR, all independently contributing to insulin resistance.
- Dietary weight loss intervention improved insulin resistance.
- Mediation analysis revealed that reductions in IHL and improvements in MVR, but not reductions in VAT or SAT, were independently associated with the improved insulin resistance observed after weight loss.
Conclusions:
- Visceral and subcutaneous adipose tissue, intrahepatic lipid content, and insulin-induced muscle microvascular recruitment have distinct, independent roles in obesity-associated insulin resistance.
- Targeting intrahepatic lipid reduction and enhancing muscle microvascular recruitment may be effective strategies for treating obesity-related insulin resistance.
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