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Cachexia is responsible for nearly 20% of all cancer‑related deaths, yet effective therapies to prevent or treat the disease are lacking. Clinical studies have shown that male patients lose weight at a faster rate than females. Additionally, an 'obesity paradox' may exist where excess adiposity may confer survival to patients with cancer cachexia. To further explore these phenomena, the aim of this study was to evaluate the role of changes of adipose tissue mass, sex status, and tumor mass on outcomes of male, female and ovariectomized (OVX) mice with C‑26 adenocarcinoma‑induced cachexia. We used EchoMRI to assess body composition and grip strength to measure muscle function. Body weights and food intake were measured daily. Mice were euthanized 19 days post‑-inoculation. Post‑necropsy, muscle fiber cross‑sectional areas were quantified and real‑time PCR was performed for genes relating to proteolysis. Survival curve, correlation and multiple linear regression analyses were performed to identify predictors of cachexia. Female and OVX tumor mice developed cachexia similarly to males, as evidenced by loss of skeletal and adipose masses, decreased grip strength, and increased proteolytic gene expression. Notably, female and OVX tumor mice had earlier onset of cachexia (≥5% weight loss) than male tumor mice. Larger tumor mass and lower adipose mass were the strongest predicting factors for increased severity of cachexia, regardless of sex or ovariectomy status. These results indicated that the impact of sex status may be subtle in comparison to the predictive effect of tumor and adipose mass in mice with C‑26‑induced cachexia.

OBJECTIVE The objective of this study was to evaluate the relationship between blood levels of adiponectin and leptin with lean body and trunk adipose mass in women with and without type 2 diabetes mellitus (T2DM). METHODS This cross-sectional study analyzed baseline data from five previous clinical studies involving postmenopausal women (n = 95). Body composition was assessed by dual-energy x-ray absorptiometry, and appendicular lean mass was calculated based on body mass index (ALMBMI). Adipokines and cytokines were measured by enzyme-linked immunosorbent assay. Linear mixed-effect models with a random study effect were used to investigate the relationship between predictors (eg, adiponectin, leptin), outcomes (eg, ALMBMI, trunk adipose mass), and co-variables (T2DM status, age, interleukin-6, and C-reactive protein). RESULTS Postmenopausal women with T2DM had lower ALMBMI than those without T2DM. There was a positive association between blood adiponectin and ALMBMI in postmenopausal women without T2DM, but no association in those with T2DM. Blood leptin was negatively associated with ALMBMI for women regardless of T2DM diagnosis. Blood adiponectin was negatively associated, whereas blood leptin was positively associated with trunk adipose mass for the entire cohort. CONCLUSIONS T2DM status moderated the relationship between blood adiponectin and ALMBMI, where blood adiponectin was positively associated with ALMBMI in postmenopausal women without T2DM, but not those with T2DM. Dysregulated metabolism in T2DM may contribute to lower muscle mass in women with T2DM, but future research is required to elucidate this mechanistic link. The negative association between blood leptin and ALMBMI was a novel finding. Future studies will need to more clearly define the relationship between these variables.

Dietary fat quality, especially the intake of specific types of fatty acids, impacts the risk of many chronic diseases, including cardiovascular diseases, certain cancers and type 2 diabetes (T2DM). A recent pooled analysis involving 20 studies from around the world revealed that higher linoleic acid (18:2n-6 LA) biomarker is associated with dose-dependent decreases in the incidence of T2DM. This latest study corroborates earlier cross-sectional studies and intervention trials showing that biomarkers of LA intake are associated with reduced risk of T2DM and better glycemic control and/or insulin sensitivity. This review highlights key clinical trials that have evaluated the role of LA in glycemia and the related condition, insulin sensitivity.

Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2(-/-)) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2(-/-) pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2(AKO)) exhibited a transient decrease in food intake like Mogat2(-/-) mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2(-/-) mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life.

As the incidence of obesity continues to increase, identifying novel nutritional therapies to enhance weight loss are needed. Raspberry ketone (RK; 4-(4-hydroxyphenyl) butan-2-one) is a bioactive phytochemical that is marketed as a weight loss supplement in the United States, yet there is scant scientific evidence demonstrating that RK promotes weight loss. The aim of the current study was to investigate the effect of RK on accumulation of adipose mass, hepatic lipid storage, and levels of plasma adiponectin in mice fed a high-fat (HF) diet. Mice were individually housed and fed a HF control diet (45% kcal from fat) for two weeks to induce weight gain, then assigned to HF control, high-dose (1.74% wt/wt) raspberry ketone (HRK), low-dose (0.25% wt/wt) raspberry ketone (LRK), or a pair-fed group (PF) fed similar food intake to LRK mice. Following five weeks of feeding, mice fed LRK and HRK diets showed reduced food intake and body weight compared to mice maintained on control diet. When normalized to body weight, mice fed HRK diet exhibited decreased inguinal fat mass and increased liver mass compared to the control group. Hepatic steatosis was lowest in mice fed HRK diet, whereas LRK diet did not have an effect when compared to the PF group. Plasma adiponectin concentration was unaffected by RK and pair-feeding. Our findings demonstrate that RK supplementation has limited benefit to adipose loss beyond reducing energy intake in mice fed a high-fat diet. The present study supports the need for appropriate study design when validating weight-loss supplements.

OBJECTIVES: Investigate the impact of dietary linoleic acid (LA) on whole-body energy metabolism, fatty acid uptake, oxylipin metabolites, and energy production machinery in skeletal muscle. METHODS: Mice were fed modified AIN-93 M diets containing 6% wt of LA or palmitic acid (PA) for 5 weeks. To address energy balance, grip strength, blood glucose, and body composition were measured weekly and indirect calorimetry was performed after 4.5 weeks of diet. To address skeletal muscle architecture, cross-sectional area was quantified in quadriceps. To determine the effect of LA diet on skeletal muscle lipids, fatty acid composition was measured in quadriceps using GC. Targeted lipidomics using LC-MS/MS was utilized to measure LA-derived oxylipins in mitochondria isolated from gastrocnemius. RESULTS: No difference in food intake, body weight, blood glucose, or body composition were observed between diet groups. Mice fed the LA diet exhibited higher heat production and lower respiratory exchange ratio, independent of ambulatory activity compared to mice fed the PA diet. Cross sectional area analysis in quadriceps muscle revealed that mice fed the LA diet had smaller muscle fibers compared to mice fed the PA diet. The LA diet increased LA level in quadriceps. Using hierarchal cluster analysis, we identified several unique patterns of oxylipins that impact insulin sensitivity and may be associated with increased mitochondrial capacity. Mice fed the LA diet exhibited a three-fold increase of oxylipin metabolites 9- and 13-HODE, and 12,13-diHOME. CONCLUSIONS: Mice fed a diet fortified in LA have increased LA in skeletal muscle, changes to skeletal muscle architecture, favorable changes to whole body energy metabolism, and increases in LA-derived oxylipins in skeletal muscle mitochondria. Our discovery that LA generates 9-HODE and 13-HODE in muscle mitochondria suggests that downstream pathways, including PPARg transactivation, may be linked with effects on muscle energy metabolism. FUNDING SOURCES: Funding was provided by the National Institutes of Health (NIH) R21CA185140, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS is supported by the Center for Muscle Health and Neuromuscular Disorders Predoctoral Research Fellowship.

cope Obesity-related metabolic dysregulation may be a link between obesity and postmenopausal breast cancer. Naringenin, a flavonoid abundant in grapefruits, displays beneficial effects on metabolic health and tumorigenesis. Here, we assessed the effects of naringenin on mammary tumor cell growth in vitro and in obese ovariectomized mice. Methods and results Naringenin inhibited cell growth, increased phosphorylation of AMP-activated protein kinase (AMPK), down-regulated CyclinD1 expression, and induced cell death in E0771 mammary tumor cells. Obese ovariectomized mice were fed a high-fat (HF), high-fat diet with low naringenin (LN; 1% naringenin) or high-fat diet with high naringenin (HN; 3% naringenin) for 2 weeks and then implanted with E0771 cells in mammary adipose tissue. Three weeks after tumor cell implantation, naringenin accumulation in tumor was higher than that in mammary adipose tissue in HN mice. HN decreased body weight, adipose mass, adipocyte size, α-smooth muscle actin mRNA in mammary adipose tissue, and mRNA of inflammatory cytokines in both mammary and perigonadal adipose tissues. Compared with mice fed HF diet, HN delayed growth of tumors early but did not alter final tumor weight. Conclusion Naringenin reduces adiposity and ameliorates adipose tissue inflammation, with a moderate inhibitory effect on tumor growth in obese ovariectomized mice.