Michelle L. Asp

Evidence for the contribution of insulin resistance to the development of cachexia in tumor‐bearing mice

Cancer cachexia is a syndrome of unintentional weight loss that is characterized by wasting of both skeletal muscle and adipose tissue. Glucose intolerance and insulin resistance have been associated with cancer cachexia. However, it is unknown whether resistance to insulin has a role in the development of cachexia. In the present study, male CD2F1 mice with colon‐26 adenocarcinoma tumors underwent an insulin tolerance test before the onset of weight loss. Compared to mice without tumors, mice with tumors had a profoundly blunted blood glucose response to insulin. Corroborating these findings, mice with tumors had decreased phosphorylation of Akt in quadriceps muscle and epididymal adipose tissue at the end of the study. Expression of Akt‐regulated genes Atrogin‐1, MuRF‐1, and Bnip3 was increased in muscle, suggesting a role for decreased insulin signaling in the induction of both proteasomal proteolysis and autophagy in cachectic muscle. Rosiglitazone treatment increased serum adiponectin, insulin sensitivity, and body weight, and decreased Atrogin‐1 and MuRF‐1 expression in the skeletal muscle of tumor‐bearing mice. In conclusion, insulin resistance is an early event in mice with cachexia induced by colon‐26 tumors. Rosiglitazone improves insulin sensitivity and decreases early markers of cachexia. These data provide evidence that insulin resistance is not only present in cachexia, but also has a role in cachexia pathogenesis. Correction of insulin resistance may be a novel therapeutic target for the treatment of cancer cachexia.

Comparison of dietary conjugated linoleic acid with safflower oil on body composition in obese postmenopausal women with type 2 diabetes mellitus

BACKGROUND Weight loss may improve glucose control in persons with type 2 diabetes. The effects of fat quality, as opposed to quantity, on weight loss are not well understood. OBJECTIVE We compared the effects of 2 dietary oils, conjugated linoleic acid (CLA) and safflower oil (SAF), on body weight and composition in obese postmenopausal women with type 2 diabetes. DESIGN This was a 36-wk randomized, double-masked, crossover study. Fifty-five obese postmenopausal women with type 2 diabetes received SAF or CLA (8 g oil/d) during two 16-wk diet periods separated by a 4-wk washout period. Subjects met monthly with the study coordinator to receive new supplements and for assessment of energy balance, biochemical endpoints, or anthropometric variables. RESULTS Thirty-five women completed the 36-wk intervention. Supplementation with CLA reduced body mass index (BMI) (P = 0.0022) and total adipose mass (P = 0.0187) without altering lean mass. The effect of CLA in lowering BMI was detected during the last 8 wk of each 16-wk diet period. In contrast, SAF had no effect on BMI or total adipose mass but reduced trunk adipose mass (P = 0.0422) and increased lean mass (P = 0.0432). SAF also significantly lowered fasting glucose (P = 0.0343) and increased adiponectin (P = 0.0051). No differences were observed in dietary energy intake, total fat intake, and fat quality in either diet period for either intervention. CONCLUSIONS Supplementation with CLA and SAF exerted different effects on BMI, total and trunk adipose mass, and lean tissue mass in obese postmenopausal women with type 2 diabetes. Supplementation with these dietary oils may be beneficial for weight loss, glycemic control, or both.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia.

Dietary protein and beef consumption predict for markers of muscle mass and nutrition status in older adults

ObjectiveTo determine the relationship of beef and protein intake to nutrition status, body composition, strength, and biochemical measures of vitamin and mineral status, inflammation and blood lipids in older adults.DesignCross-sectional observational study.SettingState of Ohio, U.S A.Participants142 adults ages 60–88.MeasurementsSubjects completed a Diet History Questionnaire, and questionnaires related to nutrition status and activity. Subjects also underwent measurements of body composition and strength, and a subset took part in a blood draw for biochemical measurements.ResultsBeef intake (g/d) was positively correlated to muscle mass measured by mid-arm muscle area (R=0.128, p=0.030). From multiple linear regression analysis, a loz/d (∼28g/d) increase in beef consumption predicts for a 2.3cm2 increase in mid-arm muscle area. Beef intake was negatively correlated to total (R=−0.179, p=0.035) and HDL (R=−0.247, p=0.004) cholesterol, and there was no association between beef and LDL-cholesterol, triglycerides, liver enzymes, or inflammatory markers. Protein intake (% of total energy) was positively correlated to nutrition status measured by the Mini Nutrition Assessment (R=0.196, p=0.020), and calf circumference (R=0.190, p=0.024), and these correlations remained when potential confounders were accounted for in multiple linear regression models. Protein intake was also positively correlated with BMI when analyzed with multiple linear regression.ConclusionsBeef intake was positively associated with mid-arm muscle area, and protein intake was positively associated with nutrition status, calf circumference, and BMI in older adults. Consuming lean cuts of beef in moderation may be a healthy way in which older adults can increase protein intake, preserve muscle mass and improve nutrition status.

c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice

SCOPE Cancer cachexia is characterized by muscle and adipose tissue wasting caused partly by chronic, systemic inflammation. Conjugated linoleic acids (CLAs) are a group of fatty acids with various properties including anti-inflammatory cis9, trans11 (c9t11)-CLA and lipid-mobilizing trans10, cis12 (t10c12)-CLA. The purpose of this study was to test whether dietary supplementation of a c9t11-CLA-rich oil (6:1 c9t11:t10c12) could attenuate wasting of muscle and adipose tissue in colon-26 adenocarcinoma-induced cachexia in mice. METHODS AND RESULTS Loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with the c9t11-CLA-rich oil. In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor-α, IL-6 receptor and the E3 ligase MuRF-1 involved in muscle proteolysis. In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression. However, expression of inflammatory cytokines and macrophage markers were not altered by tumors, or CLA supplementation. CONCLUSION These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate wasting in mice with cancer cachexia. Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation.