Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Rebecca L Scalzo ◽  
Rebecca M Foright ◽  
Sara E Hull ◽  
Leslie A Knaub ◽  
Stevi Johnson-Murguia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Endocrine Therapy ◽  
Female Mice ◽  
Adipocyte Progenitors ◽  
Adipocyte Hypertrophy ◽  
The Impact

Abstract Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

scholarly journals Breast Cancer Endocrine Therapy Exhausts Adipocyte Progenitors Promoting Weight Gain and Glucose Intolerance

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A41-A41
Author(s):  
Elizabeth A Wellberg ◽  
Stevi Johnson-Murguia ◽  
Paul S MacLean ◽  
James D Johnson ◽  
Jane E B Reusch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Endocrine Therapy ◽  
Estrogen Deprivation ◽  
Adipocyte Progenitors ◽  
Adipocyte Hypertrophy

Abstract Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use did not influence body mass index but associated with larger breast adipocyte diameter only in women with obesity, suggesting adipose tissue may be targeted by breast cancer therapies. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical murine model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from mouse adipose tissue, endocrine therapies associated with adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. We administered HFHS fed females either metformin or pioglitazone, glucose lowering drugs used to treat diabetes, or treadmill interval exercise during endocrine therapy with the goal of improving whole body metabolism. All interventions prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies may act via ER-alpha to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

scholarly journals Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

2020 ◽  
Author(s):  
Rebecca L. Scalzo ◽  
Rebecca M. Foright ◽  
Sara E. Hull ◽  
Leslie A. Knaub ◽  
Stevi Johnson-Murguia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Gain ◽  
Endocrine Therapy ◽  
Glucose Intolerance ◽  
Estrogen Deprivation ◽  
Adipocyte Progenitors ◽  
Adipocyte Hypertrophy

AbstractBreast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use associated with larger breast adipocyte diameter only in women with a BMI >30 kg/m2. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from adipose tissue, endocrine therapies induced adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. Metformin or pioglitazone, glucose lowering drugs used to treat diabetes, prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies act via ERα to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

The Impact of Exercise on DNA Methylation of Genes Associated with Type 2 Diabetes and Obesity in Human Adipose Tissue

2014 ◽  
Vol 10 (01) ◽  
pp. 64 ◽  
Author(s):  
Tina Rönn ◽  
Charlotte Ling ◽  
◽  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Human Adipose Tissue ◽  
Short Review ◽  
Methylation Pattern ◽  
Cellular Level ◽  
Genetic And Environmental Factors ◽  
The Impact

It is well established that exercise promotes health, and reduces people’s risks for developing type 2 diabetes and becoming obese. But just how exercise performs this, at a cellular level, and what molecular and physiologic steps are involved and in what order, are still not fully understood. Metabolic disorders are often influenced by interactions between genetic and environmental factors. One possible explanation for how the environment may influence the genome is through epigenetic mechanisms–that is–chemical modifications to the DNA itself. Epigenetic factors include, for example, DNA methylation, histone modifications, and different RNA-mediated processes, which all have the ability to bind to DNA or affect the chromatin structure and thereby change how specific genes are interpreted and expressed. In this short review, we focus on describing how exercise influences the genome-wide DNA methylation pattern, including candidate genes for obesity and type 2 diabetes, in human adipose tissue.

scholarly journals PDB72 The Impact on Utilities of Weight Loss and Weight Gain Among Canadian Patients With Type 2 Diabetes

2012 ◽  
Vol 15 (4) ◽  
pp. A183 ◽  
Author(s):  
S. Lane ◽  
A.R. Levy ◽  
J. Sambrook ◽  
J. Mukherjee ◽  
M. Leahy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Weight Gain ◽  
The Impact

The Impact of Body Mass Index and Type 2 Diabetes on Breast Cancer: Current Therapeutic Measures of Prevention

2004 ◽  
Vol 4 (4) ◽  
pp. 327-333 ◽  
Author(s):  
F. Resta ◽  
V. Triggiani ◽  
C. Sabba ◽  
B. Licchelli ◽  
S. Ghiyasaldin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Body Mass ◽  
Therapeutic Measures ◽  
The Impact

Diet, obesity and diabetes: a current update

2006 ◽  
Vol 112 (2) ◽  
pp. 93-111 ◽  
Author(s):  
Celia G. Walker ◽  
M. Gulrez Zariwala ◽  
Mark J. Holness ◽  
Mary C. SUGDEN
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Whole Body ◽  
Primary Defect ◽  
Obesity And Diabetes ◽  
Tissue Factors ◽  
Metabolic Conditions ◽  
The Impact

The prevalence of obesity has been increasing at a rapid rate over the last few decades. Although the primary defect can be attributed to an imbalance of energy intake over energy expenditure, the regulation of energy balance is now recognized to be complex. Adipose-tissue factors play a central role in the control of energy balance and whole-body fuel homoeostasis. The regulation of adipose-tissue function, in particular its secretion of adipokines, is impaired by increases in adipose mass associated with obesity, and with the development of insulin resistance and Type 2 diabetes. This review analyses adipose-regulated energy input and expenditure, together with the impact of dietary macronutrient composition on energy balance in relation to susceptibility to the development of obesity and Type 2 diabetes, and how these metabolic conditions may be exacerbated by the consequences of abnormal adipose function. By gaining a greater understanding of how energy balance is controlled in normal, and in obese and diabetic states, a more practical approach can be employed to prevent and better treat obesity and metabolic disorders.

scholarly journals Social Isolation Affects the Development of Obesity and Type 2 Diabetes in Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4658-4666 ◽  
Author(s):  
Katsunori Nonogaki ◽  
Kana Nozue ◽  
Yoshitomo Oka
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Social Isolation ◽  
Food Consumption ◽  
Leptin Receptor ◽  
Body Weight Gain ◽  
Kkay Mice

Social isolation is associated with increased risks of mortality and morbidity. In this study, we show that chronic individual housing accelerated body weight gain and adiposity in KK mice but not C57BL6J mice, and fully developed diabetes in KKAy mice. Individually housed KK and KKAy mice increased body weight gain over the initial 2 wk without increased daily average food consumption compared with group-housed animals. The individually housed KK and KKAy mice then gradually increased food consumption for the next 1 wk. The chronic social isolation-induced obesity (SIO) was associated with hyperleptinemia and lower plasma corticosterone and active ghrelin levels but not hyperinsulinemia. Elevated plasma leptin in the SIO suppressed expression of 5-HT2C receptor in white adipose tissue. The SIO was also associated with decreased expression of β3-adrenergic receptors in white adipose tissue and hypothalamic leptin receptor, which might be secondary to the enhanced adiposity. Interestingly, social isolation acutely reduced food consumption and body weight gain compared with group-housed obese db/db mice with leptin receptor deficiency. Social isolation-induced hyperglycemia in KKAy mice was associated with increased expression of hepatic gluconeogenetic genes independent of insulin. These findings suggest that social isolation promotes obesity due to primary decreased energy expenditure and secondary increased food consumption, which are independent of the disturbed leptin signaling, in KK mice, and develops into insulin-independent diabetes associated with increased expression of hepatic gluconeogenetic genes in KKAy mice. Thus, social isolation can be included in the environmental factors that contribute to the development of obesity and type 2 diabetes.

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