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Abstract Anthracyclines are standard‐of‐care chemotherapy for the treatment of triple‐negative breast cancer (TNBC). However, high anthracyclines cumulative doses increase heart failure risk. Designing therapeutic strategies that ameliorate cardiac toxicities without compromising oncologic efficacy are important to improve TNBC outcomes and survivorship. The purpose of this study was to determine the impact of diet on TNBC chemotherapeutic responsiveness and development of chemotherapy‐induced cardiac damage. Female BALB/c mice fed a control, Western, Mediterranean, or Western + fish oil diet were injected with 1 × 106 4T1‐luciferase TNBC into the mammary fat pad. Tumors grew for 21 days before surgical tumor resection, then mice were treated with 3.3 mg/kg i.v. doxorubicin for 3 weeks. Vevo (R) cardiac ultrasound was performed. Female nu/nu mice were placed on diets before 1 × 105 MDA‐MB‐231‐luciferase TNBC were injected via the tail vein to induce the development of lung metastases. Mice were treated with saline or 3.3 mg/kg i.v. doxorubicin for 3 weeks, and the development of metastases visualized by IVIS (R). Consumption of a high‐fat diet increased TNBC growth regardless of dietary pattern. Western diet‐fed mice developed lung metastases sooner and displayed increased lung metastatic lesion formation, which was not observed in Mediterranean diet‐fed mice. Western diet‐fed animals displayed worse cardiac function when compared with Mediterranean diet‐fed animals. Hearts from Western diet‐fed animals displayed increased fibrosis. Diet represents a modifiable component directly impacting tumor growth, antitumor chemotherapy efficacy, and cardiac toxicities. Our data suggest that the Mediterranean diet may reduce lung metastatic lesions formation and prevent the development of cardiac toxicities.

Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers of these phenotypes, a 44-animal African green monkey cohort was selected using metabolic syndrome risk criteria to represent these four clinically defined health groups. Body composition imaging and subcutaneous adipose tissue (SQ AT) biopsies were collected. Differences in adipocyte size, macrophage subtype distribution, gene expression, vascularity and fibrosis were analyzed using digital immunohistopathology, unbiased RNA-seq, endothelial CD31, and Masson’s trichrome staining, respectively. MHO AT demonstrated significant increases in M2 macrophages (p = 0.02) and upregulation of fatty acid oxidation-related terms and transcripts, including FABP7 (p = 0.01). MUO AT demonstrated downregulation of these factors and co-occurring upregulation of immune responses. These changes occurred without differences in AT distributions, adipocyte size, AT endothelial cells, collagen I deposition, or circulating cytokine levels. Without unhealthy diet consumption, healthy obesity is defined by an increased SQ AT M2/M1 macrophage ratio and lipid handling gene expression. We highlight M2 macrophages and fatty acid oxidation as targets for improving metabolic health with obesity.

Over 650 million adults are obese (body mass index ≥ 30 kg/m2) worldwide. Obesity is commonly associated with several comorbidities, including cardiovascular disease and type II diabetes. However, compiled estimates suggest that from 5 to 40% of obese individuals do not experience metabolic or cardiovascular complications. The existence of the metabolically unhealthy obese (MUO) and the metabolically healthy obese (MHO) phenotypes suggests that underlying differences exist in both tissues and overall systemic function. Macrophage accumulation in white adipose tissue (AT) in obesity is typically associated with insulin resistance. However, as plastic cells, macrophages respond to stimuli in their microenvironments, altering their polarization between pro- and anti-inflammatory phenotypes, depending on the state of their surroundings. The dichotomous nature of MHO and MUO clinical phenotypes suggests that differences in white AT function dictate local inflammatory responses by driving changes in macrophage subtypes. As obesity requires extensive AT expansion, we posit that remodeling capacity with adipose expansion potentiates favorable macrophage profiles in MHO as compared with MUO individuals. In this review, we discuss how differences in adipogenesis, AT extracellular matrix deposition and breakdown, and AT angiogenesis perpetuate altered AT macrophage profiles in MUO compared with MHO. We discuss how non-autonomous effects of remote organ systems, including the liver, gastrointestinal tract, and cardiovascular system, interact with white adipose favorably in MHO. Preferential AT macrophage profiles in MHO stem from sustained AT function and improved overall fitness and systemic health.