Metabolomic Alterations in Mammary Glands from Pubertal Mice Fed a High-Fat Diet.

Dietary malpractice is a risk factor for obesity. This study tested the hypothesis that consumption of a high-fat diet alters mammary metabolome in pubertal mice. We performed untargeted metabolomic analysis of primary metabolism on mammary glands from pubertal mice fed the AIN93G standard diet or a high-fat diet (HFD) for 3 weeks. We identified 97 metabolites for statistical comparisons. The HFD altered the amino acid metabolism considerably. This included elevated expression of branched-chain amino acids, non-essential amino acids (aspartic acid and glutamic acid), and methionine sulfoxide (oxidized methionine) and an alteration in the aminoacyl-tRNA biosynthesis pathway. Furthermore, elevations of fumaric acid and malic acid (both are citrate cycle intermediates) and glyceric acid (its phosphate derivatives are intermediates of glycolysis) in HFD-fed mice suggest an acceleration of both citrate cycle and glycolysis. Lower expression of glycerol, oleic acid, and palmitoleic acid, as well as decreased mammary expression of genes encoding lipid metabolism (Acaca, Fads1, Fasn, Scd1, and Srebf1) in HFD-fed mice indicate an attenuated lipid metabolism in the presence of adequate dietary fat. In conclusion, consumption of the HFD for 3 weeks alters metabolic profile of pubertal mammary glands. This alteration may affect mammary development and growth in pubertal mice.

Alteration in Plasma Metabolome in High-Fat Diet-Fed Monocyte Chemotactic Protein-1 Knockout Mice Bearing Pulmonary Metastases of Lewis Lung Carcinoma.

Both clinical and laboratory studies have shown that monocyte chemotactic protein-1 (MCP-1) is involved in cancer spread. To understand the role of MCP-1 in metabolism in the presence of metastasis, we conducted an untargeted metabolomic analysis of primary metabolism on plasma collected from a study showing that MCP-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma (LLC) to the lungs in mice fed a high-fat diet (HFD). In a 2 × 2 design, wild-type (WT) or Mcp-1 knockout (Mcp-1 -/-) mice maintained on the AIN93G standard diet or HFD were subcutaneously injected with LLC cells to induce lung metastasis. We identified 87 metabolites for metabolomic analysis from this study. Amino acid metabolism was altered considerably in the presence of LLC metastases with the aminoacyl-tRNA biosynthesis pathways as the leading pathway altered. The HFD modified lipid and energy metabolism, evidenced by lower contents of arachidonic acid, cholesterol, and long-chain saturated fatty acids and higher contents of glucose and pyruvic acid in mice fed the HFD. These findings were supported by network analysis showing alterations in fatty acid synthesis and glycolysis/gluconeogenesis pathways between the 2 diets. Furthermore, elevations of the citrate cycle intermediates (citric acid, fumaric acid, isocitric acid, and succinic acid) and glyceric acid in Mcp-1 -/- mice, regardless of diet, suggest the involvement of MCP-1 in mitochondrial energy metabolism during LLC metastasis. The present study demonstrates that MCP-1 deficiency and the HFD altered plasma metabolome in mice bearing LLC metastases. These findings can be useful in understanding the impact of obesity on prevention and treatment of cancer metastasis.

Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.

Metastasis is a devastating aspect of cancer. This study tested the hypothesis that metabolome of metastases differs from that of host organs by using the spontaneous metastasis model of Lewis lung carcinoma (LLC). In a 2 × 2 design, male C57BL/6 mice with or without a subcutaneous LLC inoculation were fed the standard AIN93G diet or a high-fat diet (HFD) for 12 weeks. Lung metastases from injected mice and the lungs from non-injected mice were harvested at the end of study for untargeted metabolomics of primary metabolism by using gas chromatography time-of-flight mass spectrometry. We identified 91 metabolites for metabolomic analysis. The analysis demonstrated that amino acid and energy metabolism were altered the most in LLC metastases compared to the lungs. A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from noncancer-bearing mice, reflecting the dietary fatty acid composition of the HFD. This elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in lipid metabolism during LLC metastatic progression. Understanding the differences in metabolome between pulmonary LLC metastases and the normal healthy lungs can be useful in designing targeted studies for prevention and treatment of cancer spread using this LLC spontaneous metastasis model.

Consumption of a high-fat diet alters transcriptional rhythmicity in liver from pubertal mice.

Introduction: Childhood obesity is associated with adult obesity, which is a risk factor for chronic diseases. Obesity, as an environmental cue, alters circadian rhythms. The hypothesis of this study was that consumption of a high-fat diet alters metabolic rhythms in pubertal mice. Methods: Weanling female C57BL/6NHsd mice were fed a standard AIN93G diet or a high-fat diet (HFD) for 3 weeks. Livers were collected from six-week-old mice every 4 h over a period of 48 h for transcriptome analysis. Results and discussion: The HFD altered rhythmicity of differentially rhythmic transcripts in liver. Specifically, the HFD elevated expression of circadian genes Clock, Per1, and Cry1 and genes encoding lipid metabolism Fads1 and Fads2, while decreased expression of circadian genes Bmal1 and Per2 and lipid metabolism genes Acaca, Fasn, and Scd1. Hierarchical clustering analysis of differential expression genes showed that the HFD-mediated metabolic disturbance was most active in the dark phase, ranging from Zeitgeber time 16 to 20. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes showed that the HFD up-regulated signaling pathways related to fatty acid and lipid metabolism, steroid and steroid hormone biosynthesis, amino acid metabolism and protein processing in the endoplasmic reticulum, glutathione metabolism, and ascorbate and aldarate metabolism in the dark phase. Down-regulations included MAPK pathway, lipolysis in adipocytes, Ras and Rap1 pathways, and pathways related to focal adhesion, cell adhesion molecules, and extracellular matrix-receptor interaction. In summary, the HFD altered metabolic rhythms in pubertal mice with the greatest alterations in the dark phase. These alterations may disrupt metabolic homeostasis in puberty and lead to metabolic disorders.

Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet.

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.

Exertional and CrossFit-Induced Rhabdomyolysis.

ABSTRACT: Few publications of exercise-induced rhabomyolysis currently exist in the medical literature besides case reports. However, this condition can be severe, resulting in hospitalization and IV fluid administration to prevent serious sequelae. This report describes a case of exercise-induced rhabdomyolysis caused by a CrossFit workout. A 31-year-old female presented with 2 days of bilateral upper extremity pain and soreness, which began 2 days after she completed a CrossFit workout. Workup revealed an elevated creatine phosphokinase (CPK) of 18 441 U/L, consistent with exercise-induced rhabdomyolysis, and elevated liver function tests and elevated D-dimer, although her renal function was normal. She was hospitalized for 2 days and treated with IV fluids. This case report demonstrates that CrossFit exercises can lead to rhabdomyolysis, highlighting a condition that may be underdiagnosed and underreported.

Voluntary running of defined distances alters bone microstructure in C57BL/6 mice fed a high-fat diet.

Obesity increases the risk for pathological conditions such as bone loss. On the other hand, physical exercise reduces body adiposity. To test the hypothesis that physical activity improves bone quality, we evaluated voluntary running of defined distances on trabecular and cortical microstructure in mice fed a high-fat diet (HFD). Sedentary mice were fed the standard AIN93G diet or the HFD. Mice fed the HFD remained sedentary or were assigned to unrestricted running or 75%, 50%, and 25% of unrestricted running with an average running activity at 8.3, 6.3, 4.2, and 2.1 km per day, respectively. The bone structural differences found in sedentary mice were that HFD, compared with the AIN93G diet, resulted in a lower bone volume fraction (BV/TV) and a higher structure model index (SMI) in vertebrae. Running had a greater effect on trabecular microstructure in femurs than in vertebrae; the decrease in SMI and an increase in trabecular thickness (Tb.Th) were in dose-dependent manners. Running was positively correlated with BV/TV and Tb.Th and inversely correlated with SMI in femurs. The HFD increased plasma concentrations of tartrate-resistant acid phosphatase 5b, a marker of bone resorption, in sedentary mice, while running decreased it in a dose-dependent manner. The findings show that voluntary running improves bone quality in young adult mice fed an HFD. Novelty: The high-fat diet alters bone microstructure by increasing bone resorption. Quantitative voluntary running improves bone microstructure through its attenuation of bone resorption in mice fed a high-fat diet.

High-Fat Diet Alters Circadian Rhythms in Mammary Glands of Pubertal Mice.

Childhood obesity in girls is associated with early puberty and menarche. Breast tissue exhibits circadian rhythms. These rhythms may be altered by environmental factors. We hypothesized that a high-fat diet (HFD) disrupts circadian rhythms in pubertal mammary glands. Weanling female C57BL/6 mice were fed the standard AIN93G diet or a HFD (providing 16% or 45% of energy from soybean oil) for 3 weeks. Mammary glands were harvested from 6-week-old mice every 4 h on Zeitgeber time over a 48-h period; rhythmic expressions of circadian genes and genes encoding estrogen receptor and progesterone receptor were analyzed by using the Cosinor model. HFD, compared to AIN93G diet, altered diurnal oscillations of circadian genes in pubertal mammary glands. These included changes in amplitude of Per2, Cry1 (reduced), Clock, Rev-erbα, and Per1 (elevated), a delay in acrophase (the hour at which the rhythm peaks) of Bmal1 by 2.2 h, and changes in mesor (the mean of the rhythm from peak to trough) of Bmal1, Per2, Cry1 (reduced), Rev-rebα, and Per1 (elevated). Furthermore, HFD altered diurnal expression of estrogen receptor and progesterone receptor at both mRNA and protein levels. These findings indicate that HFD alters circadian regulation in pubertal mammary glands, which may contribute to the disturbance of hormonal homeostasis and lead to early development and growth of mammary glands in pubertal mice.

Metabolome of Mammary Tumors Differs from Normal Mammary Glands But Is Not Altered by Time-restricted Feeding Under Obesogenic Conditions.

BACKGROUND/AIM: Time restricted feeding (TRF) mitigates the high-fat diet-enhanced mammary tumorigenesis in a MMTV-PyMT breast cancer model. MATERIALS AND METHODS: We performed untargeted metabolomic and targeted transcriptomic analyses on mammary tumors from MMTV-PyMT mice fed a standard AIN93G diet, a high-fat diet (HFD), or HFD with TRF (12 h, dark phase) and mammary glands from wild-type mice fed the AIN93G diet. RESULTS: The metabolic profile of mammary tumors differed from that of mammary glands; there was no impact of TRF upon tumor metabolome. TRF did reduce elevated expression of Hmgcr, Srebp1, Fads2, and Ppard in mammary tumors, indicating a down-regulation of lipid metabolism. CONCLUSION: The null effect of TRF on the metabolomic profile does not rule out changes in more refined intracellular signaling pathways. It suggests that the protection of TRF against mammary tumorigenesis may rely upon its action on the host rather than a direct effect on tumor metabolism.

Dietary Selenium Supplementation Does Not Attenuate Mammary Tumorigenesis-Mediated Bone Loss in Male MMTV-PyMT Mice.

Bone wasting occurs during the progression of breast cancer and contributes to breast cancer mortality. We evaluated the effect of methylseleninic acid (MSeA), an anti-carcinogenic form of selenium, on bone microstructural changes in the presence of mammary tumors in a male breast cancer model of mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT). In this study, we performed microcomputed tomographic analysis of femurs and vertebrae collected from a study showing that dietary supplementation with MSeA reduces mammary tumorigenesis in male mice. Compared to age-matched, non-tumor-bearing mice (MMTV-PyMT negative), the presence of mammary tumors significantly reduced the bone volume fraction, trabecular thickness, and bone mineral density while it increased the structure model index in femurs, but not in vertebrae. Moreover, mammary tumorigenesis decreased plasma concentrations of osteocalcin. Supplementation with MSeA did not affect these changes in MMTV-PyMT mice. In conclusion, mammary tumorigenesis caused bone loss in MMTV-PyMT mice. However, dietary supplementation with MSeA did not attenuate mammary tumor-associated bone loss in this model of male breast cancer.

Adipose monocyte chemotactic protein-1 deficiency reduces high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice.

Monocyte chemotactic protein-1 (MCP-1) is an adipokine with demonstrated carcinogenic potential. However, there is a lack of evidence whether adipose-produced MCP-1 contributes to breast cancer. We tested the hypothesis that adipose-produced MCP-1 contributes to mammary tumorigenesis in this study. In a breast cancer model of mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT), mice with or without adipose MCP-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the standard AIN93G diet (16% of energy from soybean oil) or a high-fat diet (HFD, 45% of energy from soybean oil). Adipose MCP-1 knockout reduced Mcp-1 expression in adipose tissue and concentrations of MCP-1 in plasma. Mcp-1-/- mice fed the HFD had less body fat than their WT counterparts. Adipose MCP-1 knockout attenuated HFD-enhanced mammary tumorigenesis, evidenced by lower mammary tumor volume. Furthermore, Mcp-1-/- mice, regardless of diet, had a longer tumor latency and less tumor weight than WT mice. When fed the HFD, Mcp-1-/- mice, compared to WT mice, exhibited lower concentrations of insulin, leptin, resistin, vascular endothelial growth factor and hepatic growth factor in plasma. In summary, adipose MCP-1 deficiency attenuated HFD-enhanced MMTV-PyMT mammary tumorigenesis. This attenuation can be attributed to less body adiposity, improvement in insulin sensitivity and down-regulation in protumorigenic inflammation cytokines and angiogenic factors in Mcp-1-/- mice. It concludes that adipose-produced MCP-1 contributes to mammary tumorigenesis in the MMTV-PyMT mouse model.

Adipose-specific Monocyte Chemotactic Protein-1 Deficiency Reduces Pulmonary Metastasis of Lewis Lung Carcinoma in Mice.

AIM: Monocyte chemotactic protein-1 (MCP1) is a potent adipokine. This study tested the hypothesis that adipose-produced MCP1 contributes to metastasis. MATERIALS AND METHODS: In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male adipose MCP1-deficient (Mcp1-/-) and wild-type (WT) mice were fed the AIN93G diet or a high-fat diet (HFD) for 11 weeks. Lung metastasis from a subcutaneous tumor was the primary endpoint. RESULTS: The adipose expression of MCP1 was lower in Mcp1-/- mice than in WT controls. The HFD increased the number of lung metastases in WT mice. The number of metastasis was significantly lower in the HFD-fed Mcp1-/- mice than in the HFD-fed WT mice. Compared to the WT mice, adipose MCP1 deficiency lowered plasma concentrations of insulin, proinflammatory adipokines (leptin, plasminogen activator inhibitor-1, and resistin), and angiogenic markers (vascular endothelial growth factor, hepatocyte growth factor, and angiopoietin-2). CONCLUSION: Adipose MCP1 deficiency attenuates HFD-enhanced pulmonary metastasis of LLC.

Time-restricted Feeding Attenuates High-fat Diet-enhanced Spontaneous Metastasis of Lewis Lung Carcinoma in Mice.

BACKGROUND/AIM: Obesity is a risk factor for cancer. Disruption of the daily feeding and fasting rhythm can contribute to obesity. This study tested the hypothesis that time-restricted feeding (TRF) attenuates obesity-enhanced metastasis. MATERIALS AND METHODS: In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were fed the standard AIN93G diet or a high-fat diet (HFD) with or without dark-phase restricted feeding (12 h per day) for 10 weeks. Pulmonary metastases from a subcutaneous tumor were quantified. RESULTS: The number and size of lung metastases were greater in the HFD group than in the AIN93G group, but did not differ between the TRF and AIN93G groups. TRF prevented HFD-induced increases in plasma concentrations of glucose, insulin, proinflammatory cytokines (leptin, monocyte chemotactic protein-1, plasminogen activator inhibitor-1), and angiogenic factors (angiopoietin-2, hepatic growth factor, vascular endothelial growth factor). CONCLUSION: TRF attenuates the HFD-enhanced spontaneous metastasis of LLC in mice.

A high-sucrose diet does not enhance spontaneous metastasis of Lewis lung carcinoma in mice.

A high energy intake contributes to obesity, a risk factor for cancer. We previously reported that an excessive intake of dietary fat enhances malignant spread in mice. This study tested the hypothesis that consumption of a diet with an excessive amount of sucrose enhances metastasis. In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were maintained on an AIN93G, a high-fat, or a high-sucrose diet for the duration of the study. Pulmonary metastases from a primary tumor, established by a subcutaneous injection of LLC cells, were quantified. There were no differences in energy intake among the 3 groups. The percent body fat mass of the high-sucrose group, while higher than that of the AIN93G group, was lower than that of the high-fat group. The number and size of lung metastases were significantly higher in the high-fat group than in the AIN93G group; these measurements in the high-sucrose group remained similar to those in the AIN93G group. Hepatic concentrations of triacylglycerols and plasma concentrations of insulin, proinflammatory cytokines (leptin, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1) and angiogenic factors (vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1) in the high-sucrose group were significantly lower than those in the high-fat group. In conclusion, the high-sucrose diet does not enhance spontaneous metastasis of LLC. This null effect may be due to the inadequate production of tumorigenic proinflammatory cytokines and angiogenic factors by the high-sucrose diet compared to the high-fat diet.

Lipidomic Impacts of an Obesogenic Diet Upon Lewis Lung Carcinoma in Mice.

Metabolic reprogramming of lipid metabolism is a hallmark of cancer. Consumption of a high-fat obesogenic diet enhances spontaneous metastasis using a Lewis lung carcinoma (LLC) model. In order to gain further insights into the mechanisms by which dietary fats impact cancer progression, we conducted a lipidomic analysis of primary tumors originated from LLC from mice fed with a standard AIN93G diet or a soybean oil-based high-fat diet (HFD). Hierarchical clustering heatmap analysis of phosphatidylcholine (PC) lipids and phosphatidylethanolamine (PE) lipids demonstrated an increase in polyunsaturated fatty acids (PUFA)-containing phospholipids and a decrease in monounsaturated fatty acids (MUFA)-containing lipids in tumors from mice fed the HFD. The quantities of 51 PC and 24 PE lipids differed in primary tumors of LLC from mice fed the control diet and the HFD. Analysis of triacylglycerol (TAG) lipids identified differences in 32 TAG (by brutto structure) between the two groups; TAG analysis by neutral loss identified 46 PUFA-containing TAG species that were higher in mice fed with the HFD than in the controls. Intake of the HFD did not alter the expression of the de novo lipogenesis enzymes (fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase-1). Our results demonstrate that the dietary fatty acid composition of the HFD is reflected in the higher order lipidomic composition of primary tumors. Subsequent studies are needed to investigate how these lipidomic changes may be used for targeted dietary intervention to reduce tumor growth and malignant progression.

An Update on Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: a Review of the Current Literature.

PURPOSE OF REVIEW: This review will summarize the most current literature on the clinical impact, epidemiology, risk factors, screening recommendations, predictors of outcomes, and treatment options in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). RECENT FINDINGS: PAH continues to be a major cause of morbidity and mortality in SSc. Many risk factors and predictors of outcomes have been identified in patients with SSc including clinical, hemodynamic, and laboratory parameters. Screening for PAH in SSc patients is important and screening algorithms have been developed. Despite many available treatment options for PAH, prognosis remains poor. Awareness of risk factors, early detection, and up-front combination treatment are important considerations in SSc-PAH and may lead to improved outcomes. Further research to develop better biomarkers and therapies is needed to continue to improve survival and outcomes in patients with SSc-PAH.

Dietary Supplementation with Methylseleninic Acid Inhibits Mammary Tumorigenesis and Metastasis in Male MMTV-PyMT Mice.

Male breast cancer, which makes up approximately 1% of all breast cancers, is an aggressive disease with poor prognosis. We investigated the effects of dietary supplementation with selenium in the form of methylseleninic acid [(MSeA) 2.5 mg selenium/kg] on mammary tumorigenesis in male MMTV-PyMT mice. The mammary tumor latency was 14.6 weeks for the MSeA-fed group and 13.8 weeks for the controls fed the AIN93G diet (p < 0.05). Dietary supplementation with MSeA, versus the control, resulted in a 72% reduction in tumor progression, a 46% reduction in both final volume and weight of mammary tumors, and a 70% reduction in the number of lung metastases. Mammary tumorigenesis in MMTV-PyMT mice, versus non-tumor-bearing wild-type mice, resulted in significant increases in concentrations of plasminogen activator inhibitor-1, urokinase plasminogen activator, monocyte chemotactic protein-1, and vascular endothelial growth factor, but not aromatase and estrogen, in the plasma. Concentrations of all variables mentioned above in both plasma and mammary tumors were lower in MSeA-fed mice. Mammary tumorigenesis reduced plasma levels of adiponectin compared to non-tumor-bearing controls. Adiponectin concentrations in mammary tumors, but not in plasma, were higher in MSeA-fed mice than in controls. In summary, dietary supplementation with selenium in the form of MSeA inhibits mammary tumorigenesis and its pulmonary metastasis in male MMTV-PyMT mice.

Exertional and CrossFit-Induced Rhabdomyolysis.

Few publications of exercise-induced rhabomyolysis currently exist in the medical literature besides case reports. However, this condition can be severe, resulting in hospitalization and IV fluid administration to prevent serious sequelae. This report describes a case of exercise-induced rhabdomyolysis caused by a CrossFit workout. A 31-year-old female presented with 2 days of bilateral upper extremity pain and soreness, which began 2 days after she completed a CrossFit workout. Workup revealed an elevated creatine phosphokinase (CPK) of 18 441 U/L, consistent with exercise-induced rhabdomyolysis, and elevated liver function tests and elevated D-dimer, although her renal function was normal. She was hospitalized for 2 days and treated with IV fluids. This case report demonstrates that CrossFit exercises can lead to rhabdomyolysis, highlighting a condition that may be underdiagnosed and underreported.

Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet.

This study investigated the effect of voluntary running of defined distances on body adiposity in male C57BL/6 mice fed a high-fat diet. Mice were assigned to 6 groups and fed a standard AIN93G diet (sedentary) or a modified high-fat AIN93G diet (sedentary; unrestricted running; or 75%, 50%, or 25% of unrestricted running) for 12 weeks. The average running distance was 8.3, 6.3, 4.2, and 2.1 km/day for the unrestricted, 75%, 50%, and 25% of unrestricted runners, respectively. Body adiposity was 46% higher in sedentary mice when fed the high-fat diet instead of the standard diet. Running decreased adiposity in mice fed the high-fat diet in a dose-dependent manner but with no significant difference between sedentary mice and those running 2.1 km/day. In sedentary mice, the high-fat instead of the standard diet increased insulin resistance, hepatic triacylglycerides, and adipose and plasma concentrations of leptin and monocyte chemotactic protein-1 (MCP-1). Running reduced these variables in a dose-dependent manner. Adipose adiponectin was lowest in sedentary mice fed the high-fat diet; running raised adiponectin in both adipose tissue and plasma. Running 8.3 and 6.3 km/day had the greatest, but similar, effects on the aforementioned variables. Running 2.1 km/day did not affect these variables except, when compared with sedentariness, it significantly decreased MCP-1. The findings showed that running 6.3 kg/day was optimal for reducing adiposity and associated inflammation that was increased in mice by feeding a high-fat diet. The findings suggest that voluntary running of defined distances may counteract the obesogenic effects of a high-fat diet.