High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages

Bader, Jackie E.; Carson, Meredith S.; Enos, Reilly T.; Velázquez, Kandy T.; Sougiannis, Alexander T.; Singh, Udai P.; Becker, William; Nagarkatti, Mitzi; Fan, Daping; Murphy, Angela

doi:10.18632/oncotarget.27832

Cited by 12 publications

(11 citation statements)

References 67 publications

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“…Within males, HFD feeding increased the gene expression of all inflammatory mediators: MCP-1, TNF-α, TLR2, CXCL14, IL-10 and macrophage markers measured: F4/80 (general macrophage marker), CD11c (M1 macrophage marker), and CD206 (M2 macrophage marker) (P < 0.05). As it has already been established that a sexual dichotomy exists with respect to the inflammatory response to HFD consumption between males and females 35 , it was not surprising to find that HFD-fed females only displayed increased gonadal MCP-1, TNF-α, and CD11c gene expression relative to LFD-fed mice (P < 0.05), but not TLR2, CXCL14, IL-10, F4/80, and CD206 mRNA content. Given that estrogen is known to play an important role in regulating inflammatory and metabolic processes 36 , 37 , it was anticipated and confirmed that estrogen deficiency in a HFD setting increased the gene expression of all inflammatory markers measured relative to intact female HFD mice (P < 0.05).…”

Section: Resultsmentioning

confidence: 84%

Congenital adiponectin deficiency mitigates high-fat-diet-induced obesity in gonadally intact male and female, but not in ovariectomized mice

Unger

Al-Adhami

Hope

et al. 2022

Sci Rep

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Epidemiological literature indicates that women are less susceptible to type II diabetes (T2D) than males. The general consensus is that estrogen is protective, whereas its deficiency in post-menopause is associated with adiposity and impaired insulin sensitivity. However, epidemiological data suggests that males are more prone to developing T2D, and at a lower BMI, compared to females during post-menopausal years; suggesting that another factor, other than estrogen, protects females. We proposed to determine if adiponectin (APN) serves as this protective factor. An initial experiment was performed in which gonadally intact male and female mice were fed either a purified low-fat diet (LFD) or high-fat diet (HFD) (40% kcals from fat) for 16 weeks. An additional group of HFD ovariectomy (OVX) mice were included to assess estrogen deficiency’s impact on obesity. Body composition, adipose tissue inflammation, ectopic lipid accumulation as well as glucose metabolism and insulin resistance were assessed. In corroboration with previous data, estrogen deficiency (OVX) exacerbated HFD-induced obesity in female mice. However, despite a higher body fat percentage and a similar degree of hepatic and skeletal muscle lipid accumulation, female OVX HFD-fed mice exhibited enhanced insulin sensitivity relative to HFD-fed males. Therefore, a subsequent HFD experiment was performed utilizing male and female (both gonadally intact and OVX) APN deficient mice (APN−/−) and wildtype littermates to determine if APN is the factor which protects OVX females from the similar degree of metabolic dysfunction as males in the setting of obesity. Indirect calorimetry was used to determine observed phenotype differences. APN deficiency limited adiposity and mitigated HFD-induced insulin resistance and adipose tissue inflammation in gonadally intact male and female, but not in OVX mice. Using indirect calorimetry, we uncovered that slight, but non-statistically significant differences in food intake and energy expenditure leading to a net difference in energy balance likely explain the reduced body weight exhibited by male APN-deficient mice. In conclusion, congenital APN deficiency is protective against obesity development in gonadally intact mice, however, in the setting of estrogen deficiency (OVX) this is not true. These findings suggest that gonadal status dictates the protective effects of congenital APN deficiency in the setting of HFD-induced obesity.

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Section: Resultsmentioning

confidence: 84%

Congenital adiponectin deficiency mitigates high-fat-diet-induced obesity in gonadally intact male and female, but not in ovariectomized mice

Unger

Al-Adhami

Hope

et al. 2022

Sci Rep

Self Cite

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“…This should be taken into consideration when examining the results of the study. We focused our study in male mice as female mice do not show as robust response with respect to adipose tissue inflammation resulting from HFD consumption 15 …”

Section: Methodsmentioning

confidence: 99%

“…We focused our study in male mice as female mice do not show as robust response with respect to adipose tissue inflammation resulting from HFD consumption. 15 …”

Section: Methodsmentioning

confidence: 99%

Macrophage tumor necrosis factor‐alpha deletion does not protect against obesity‐associated metabolic dysfunction

et al. 2021

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“…The findings revealed markedly accelerated subcutaneous tumor growth in obese females lacking ovarian hormones. The potential mechanisms driving obesity-mediated enhancement of cancer growth in this study mainly included TAMs-associated adipose inflammation and the release of adipose specific IGF-1 ( 6 ). In addition, obesity could be associated with cancer drug resistance.…”

Section: Igf-1r Signaling: a Key Link Between Metabolic Syndrome And ...mentioning

confidence: 99%

“…According to emerging evidence from molecular studies, the tumor microenvironment uses key paracrine factors such as insulin-like growth factor 1 (IGF-1) to fuel tumorigenesis (1)(2)(3). Certainly, in the current global obesity epidemic, IGFs have attracted attention for their potential role as a link between cancer and insulin resistance syndrome (4)(5)(6), a metabolic syndrome of increasing incidence that encompasses hyper/ hypoinsulinemia, hyper/hypoglycemia, dyslipidemia and hypertension, with a marked increase in risk to develop diabetes mellitus, cardiovascular diseases, and cancer (7)(8)(9)(10). Notably, recent reports show that antidiabetic drugs, such as metformin, can mediate anticancer effects partly by silencing IGF-1 expression (9,10).…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

Kamdje¹,

Etet

Kipanyula

et al. 2022

Front. Endocrinol.

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The tumor microenvironment fuels tumorigenesis and induces the development of resistance to anticancer drugs. A growing number of reports support that the tumor microenvironment mediates these deleterious effects partly by overexpressing insulin-like growth factor 1 (IGF-1). IGF-1 is known for its role to support cancer progression and metastasis through the promotion of neovascularization in transforming tissues, and the promotion of the proliferation, maintenance and migration of malignant cells. Anti-IGF therapies showed potent anticancer effects and the ability to suppress cancer resistance to various chemotherapy drugs in in vivo and in vitro preclinical studies. However, high toxicity and resistance to these agents are increasingly being reported in clinical trials. We review data supporting the notion that tumor microenvironment mediates tumorigenesis partly through IGF-1 signaling pathway. We also discuss the therapeutic potential of IGF-1 receptor targeting, with special emphasis on the ability of IGF-R silencing to overcome chemotherapy drug resistance, as well as the challenges for clinical use of anti-IGF-1R therapies.

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High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages

Cited by 12 publications

References 67 publications

Congenital adiponectin deficiency mitigates high-fat-diet-induced obesity in gonadally intact male and female, but not in ovariectomized mice

Congenital adiponectin deficiency mitigates high-fat-diet-induced obesity in gonadally intact male and female, but not in ovariectomized mice

Macrophage tumor necrosis factor‐alpha deletion does not protect against obesity‐associated metabolic dysfunction

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

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