A Prospective Study of Obesity, Metabolic Health, and Cancer Mortality

Akinyemiju, Tomi; Moore, Justin Xavier; Pisu, Maria; Judd, Suzanne E.; Goodman, Michael; Shikany, James M.; Howard, Virginia J.; Safford, Monika; Gilchrist, Susan C.

doi:10.1002/oby.22067

Cited by 42 publications

(31 citation statements)

References 41 publications

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“…It is also well established in epidemiologic studies that metabolic conditions such as obesity, 342 metabolic syndrome and diabetes are important risk factors for breast cancer and other 343 malignancies [37][38][39][40] and data from animal models offer support to those findings [41,42]. In 344 line with that, we demonstrated that a milieu of metabolic dysfunction and altered stromal 345 microenvironment creates conditions for increased proliferation and survival of both normal and 346 tumorigenic mammary cells as demonstrated by our transplantation studies.…”

supporting

confidence: 78%

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Fontelles¹,

Cruz²,

Gonsiewski³

et al. 2020

Preprint

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21Background: While genetics explains some familial breast cancer cases, we showed that 22 environmentally-induced epigenetic inheritance of breast cancer can also occur in rodent 23 models. We previously reported that paternal consumption of a high-fat diet and ensuing obesity 24 increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear 25 whether paternal-induced programming of breast cancer in daughters is associated with systemic 26 alterations or mammary epithelium-specific factors. It also remains to be determined whether 27 the ancestrally programmed breast cancer predisposition in F1 progeny can be transmitted to 28 subsequent generations. 29Methods: Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) 30 for seven weeks and then mated with female mice (F0) reared on a CO diet. The resulting 31 offspring (F1), also exclusively fed CO diet, were either used for mammary gland and tumor 32 transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, 33 female mice were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted 34 from F0 or F1 males sperm was used for small RNA-Seq analysis. 35Results: Mammary glands from F1 CO female offspring exhibited enhanced development when 36 transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, 37 epithelial branching and elongation, compared to CO females that received a CO mammary 38 gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted 39 into OID females [OID(CO.T)] displayed improved growth with a higher proliferation/apoptosis 40 rate. We also found that granddaughters (F2) from the OID grand-paternal germline showed 41 accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast 42 cancer predisposition to the F2 generation through OID male germline was associated with 43 alterations in specific sperm tRNA fragments (tRF) in both F0 and F1 males. 44 Conclusions:Our findings indicate that systemic metabolic and mammary stromal alterations 45 are the most significant contributors to paternal programming of mammary gland development 46 and cancer predisposition in female offspring rather than mammary epithelium confined factors. 47Our data also show breast cancer predisposition in OID daughters can be transmitted to 48 subsequent generations and could explain some familial cancers, if confirmed in humans. 49 50 Insulin tolerance test (ITT) was performed after the mice fasted for 6 h, according to the method 113 described by Takada et al [21]. The insulin load (75 mU/100 g body weight) was injected as a 114 bolus, and the blood glucose levels were determined at 0, 3, 6, 9, 12, and 30 minutes after 115 injection in female offspring. The area under the curve (AUC) was calculated according to the 116 trapezoid rule. Differences in ITT were analyzed using two-way ANOVA (group, time), 117 followed by post-hoc analyses.

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supporting

confidence: 78%

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Fontelles¹,

Cruz²,

Gonsiewski³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…AT excess is generated by the imbalance between calories intake and energy expenditure, where energy excess is stored mainly in AT, favoring its expansion. Obesity and overweight, especially abdominal fat accumulation, are major risk factors for a number of noncommunicable diseases including cardiovascular disorders, dyslipidemia, insulin resistance and certain cancers, among others [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

M1 macrophage subtypes activation and adipocyte dysfunction worsen during prolonged consumption of a fructose-rich diet

Gambaro

Zubiría

Portales

et al. 2018

The Journal of Nutritional Biochemistry

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Fructose-rich diet (FRD) has been associated with obesity development, which is characterized by adipocytes hypertrophy and chronic low-grade inflammation. Interaction of adipocytes and immune cells plays a key role in adipose tissue (AT) alterations in obesity. We assessed the metabolic and immune impairments in AT in a murine obesity model induced by FRD at different periods. Adult Swiss mice were divided into groups of 6 and 10 weeks of fructose (FRD 6wk, FRD 10wk) or water intake (CTR 6wk, CTR 10wk). FRD induced increased in body weight, epidydimal AT mass, and plasmatic and liver Tg, and impaired insulin sensitivity. Also, hypertrophic adipocytes from FRD 6wk-10wk mice showed higher IL-6 when stimulated with LPS and leptin secretion. Several of these alterations worsened in FRD 10wk. Regarding AT inflammation, FRD mice have increased TNFα, IL-6 and IL1β, and decrease in IL-10 and CD206 mRNA levels. Using CD11b, LY6C, CD11c and CD206 as macrophages markers, we identified for first time in AT M1 (M1a: Ly6CCD11cCD206 and M1b: Ly6CCD11cCD206) and M2 subtypes (Ly6CCD11cCD206). M1a phenotype increased from 6 weeks onward, while Ly6C M1b phenotype increased only after 10 weeks. Finally, co-culture of RAW264.7 (monocytes cell line) and CTR or FRD adipocytes showed that FRD 10wk adipocytes increased IL-6 expression in non- or LPS-stimulated monocytes. Our results showed that AT dysfunction got worse as the period of fructose consumption was longer. Inflammatory macrophage subtypes increased depending on the period of FRD intake, and hypertrophic adipocytes were able to create an environment that favored M1 phenotype in vitro.

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“…Many studies have investigated the influence of specific metabolic obesity phenotypes on cancers, such as colorectal cancer and breast cancer. 15,16,29,31 Kim et al were the first to explore the incidence of PCa according to the BMI and metabolic status. 32 Both obesity and metabolic disorders increased the risk of PCa, and the risk increased according to the number of components of MetS.…”

Section: Discussionmentioning

confidence: 99%

<p>Metabolically Abnormal Obesity Increases the Risk of Advanced Prostate Cancer in Chinese Patients Undergoing Radical Prostatectomy</p>

Liu¹,

Li²,

Wang³

et al. 2020

CMAR

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Background: To investigate the pathological risk of prostate cancer (PCa) according to the obesity and metabolic status of Chinese patients undergoing radical prostatectomy. Materials and Methods: We performed a retrospective cross-sectional study of 1016 patients with PCa who underwent radical prostatectomy and whose metabolic status and body mass index were examined. Multivariate logistic regression analysis was performed to examine the relationship between different metabolic obesity phenotypes and the pathological outcomes of PCa. Results: Among 1016 men, 551 (54.2%), 106 (10.4%), 238 (23.4%), and 121 (11.9%) were assigned to the metabolically healthy and normal weight (MHNW) group, metabolically abnormal but normal weight (MANW) group, metabolically healthy but overweight or obese (MHO) group, and metabolically abnormal and overweight or obese (MAO) group, respectively. Compared with the MHNW group, the MAO group had a significantly greater risk of a higher prostatectomy Gleason score [odds ratio (OR), 1.907; 95% confidence interval (95% CI), 1.144-3.182], pathological stage (OR, 1.606; 95% CI, 1.035-2.493), and seminal vesicle invasion (OR, 1.673; 95% CI, 1.041-2.687). In contrast, the ORs were not increased in the MHO or MANW group. In the context of normal weight, metabolic disorders were associated with lymph node involvement. The metabolic status and body mass index were not associated with extracapsular extension or surgical margins in any of the four groups. Conclusion: The MAO phenotype is associated with aggressive PCa, including a higher prostatectomy Gleason score, pathological stage, and seminal vesicle invasion and might also be associated with disease progression. Obesity and metabolic disorders act synergistically to increase the pathological risk of PCa.

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A Prospective Study of Obesity, Metabolic Health, and Cancer Mortality

Cited by 42 publications

References 41 publications

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

M1 macrophage subtypes activation and adipocyte dysfunction worsen during prolonged consumption of a fructose-rich diet

<p>Metabolically Abnormal Obesity Increases the Risk of Advanced Prostate Cancer in Chinese Patients Undergoing Radical Prostatectomy</p>

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