A prospective evaluation of clinical and genetic predictors of weight changes in breast cancer survivors.

BACKGROUND: Postdiagnosis weight gain in patients with breast cancer has been associated with increased cancer recurrence and mortality. This study was designed to identify risk factors for weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: The weight of 393 patients with breast cancer from the Northwestern Robert H. Lurie Cancer Center was measured over a 2-year period from diagnosis, with body mass index (BMI) change over 18 months as the primary endpoint. Demographics, clinical factors, treatment methods, as well as tumor characteristics were also recorded; and a lifestyle questionnaire was conducted. Blood samples were genotyped for 16 single nucleotide polymorphisms in FTO, adiponectin pathway genes (ADIPOQ, ADIPOR1), and FNDC5. Serum leptin, adiponectin, and irisin levels also were measured. RESULTS: Mean ± standard deviation 18-month BMI changes were 0.68 ± 1.42, 0.98 ± 1.62, 0.79 ± 1.74, and -0.44 ± 1.58 kg/m2 for patients ages <40, 40 to 49, 50 to 59, and ≥60 years, respectively. The optimal multivariable model for 18-month BMI change contained the predictors age, height, and endocrine therapy, but only age was statistically significant, with a 0.04 kg/m2 increase in 18-month BMI change per younger year of age. Single nucleotide polymorphisms in ADIPOR1, FTO, and FNDC5 were associated with 18-month BMI change, and the first 2 remained significant after adjusting for the optimal clinical model (all P < .05). CONCLUSIONS: Women age 60 years and younger at the time of breast cancer diagnosis who have an obesity genetic risk model are at increased risk for weight gain after treatment and should be targeted for weight-maintenance interventions. Cancer 2017;123:2413-21. © 2017 American Cancer Society.

Diet quality and diet patterns in relation to circulating cardiometabolic biomarkers.

BACKGROUND & AIMS: We examined the effects of diet quality and dietary patterns in relation to biomarkers of risk including leptin, soluble intracellular adhesion molecule 1 (sICAM-1), C-reactive protein (CRP), and irisin. METHODS: We analyzed data from 196 adults cross-sectionally. Dietary patterns were identified by factor analysis and diet quality scores were generated using a validated food-frequency questionnaire. RESULTS: Both the alternate healthy eating index-2010 (AHEI-2010) and the Dietary Approaches to Stop Hypertension (DASH) scores were negatively related to CRP, even after controlling for body mass index and total energy intake. Similarly, the prudent diet pattern was negatively related to leptin, sICAM-1, and CRP, whereas the Western diet pattern showed positive associations with these markers; however, after adjusting for all confounders, the associations only remained significant for leptin and sICAM-1. Irisin was positively associated with DASH and the prudent diet after controlling for all confounders (standardized ß = 0.23, P = 0.030; standardized ß = 0.25, P = 0.021, respectively). Irisin showed positive associations with increasing fruit consumption, whereas the levels of irisin decreased as meat consumption increased. CONCLUSIONS: Irisin was directly associated with healthy diet types and patterns. Further studies regarding these mechanisms are warranted. This trial is registered at http://www.clinicaltrials.gov. Identifier: NCT01853332.

Intracellular leptin signaling following effective weight loss.

AIM: To investigate the effect of ex-vivo leptin treatment before and after weight loss on key-molecules of intracellular leptin signaling in peripheral blood mononuclear cells (PBMCs) of obese women. MATERIALS AND METHODS: Five healthy obese women underwent a 12-week medical nutrition treatment aiming at inducing 10% weight loss. Isolated PBMCs at baseline, and at weeks 8 and 12 were treated with increasing leptin doses (0, 25 and 75 ng/ml) for 30 min. The phosphorylation of signal transducer and activator of transcription (STAT)3, extracellular-signal-regulated kinase (ERK), protein kinase B (Akt) and 5' adenosine monophosphate-activated protein kinase (AMPK) of PBMCs was analyzed using Western blotting. RESULTS: Women lost 10 ± 1% and 13 ± 1% of weight at week 8 and 12, respectively. Circulating leptin and insulin significantly decreased from 39.5 ± 7.7 to 12.2 ± 2.4 ng/ml (p = 0.026) and from 13.0 ± 1.6 to 5.4 ± 0.9 µU/ml (p = 0.005) at week 12, respectively. In the ex vivo study, a significant decrease in STAT3 phosphorylation was observed in the control group after weight loss. Treatment of PBMCs with leptin 75 ng/ml increased significantly ERK, STAT3 and Akt phosphorylation, but no weight loss induced change was observed in response to leptin treatment ex vivo. CONCLUSIONS: A 10%-15% weight loss decreases baseline STAT3 phosphorylation ex vivo, but does not alter the effect of increasing doses of leptin on the incremental intracellular phosphorylation of STAT3, ERK, Akt and AMPK. Supraphysiologic leptin doses (75 ng/ml) result in higher protein phosphorylation compared to either physiologic doses or no treatment, before and after weight loss.

Diet quality is associated with circulating C-reactive protein but not irisin levels in humans.

OBJECTIVE: Adherence to a healthy diet has been shown to decrease the incidence of obesity and associated comorbidities. C-reactive protein (CRP) is an established inflammatory marker and irisin was recently identified as a molecule which may play a role in energy regulation and obesity but whether diet alters irisin levels remains unknown. We aimed to investigate the association between circulating irisin, leptin, and CRP levels and dietary quantity and quality using the Alternate Healthy Eating Index (AHEI) and the Alternate Mediterranean Diet Score (aMED). MATERIALS/METHODS: The study evaluated dietary data and biomarker levels of 151 participants between 2009 and 2011 (71 male vs. 80 female, over 35 years old, obese 43.7%). AHEI and aMED scores were calculated based on data derived from self-administered 110-item food-frequency questionnaires estimating usual nutrient intake over the past year. Cross-sectional associations between dietary quantity, quality, body composition by bioelectric impedance, and biomarker levels including irisin, leptin, and CRP after fasting were assessed. RESULTS: CRP, but not irisin, was negatively correlated with AHEI (r=-0.34) and aMED (r=-0.31). Irisin was positively correlated with BMI (r=0.22), fat mass (r=0.21), waist circumference (r=0.24), waist-hip ratio (r=0.20), leptin (r=0.32), and CRP (r=0.25). Participants with the highest AHEI scores tended to have 11.6% lower concentrations of irisin (P for trend =0.09), but they were not significant after adjustment for potential confounders. Better diet quality was associated with lower CRP concentrations (P for trend=0.02) in multivariate model. Percentage of energy from carbohydrate was inversely associated with CRP. CONCLUSIONS: Unlike CRP, irisin is not associated with dietary quality or quantity.

Early life adversity is associated with elevated levels of circulating leptin, irisin, and decreased levels of adiponectin in midlife adults.

CONTEXT: Early-life adversity, defined as physical, emotional, or sexual abuse and neglect before 18 years of age, is associated with metabolic syndrome, obesity, and type 2 diabetes mellitus in adult life. However, the underlying mechanism is not fully understood, and whether adipomyokines are associated with early-life adversity independent of other factors such as body mass index, psychosocial risks, and health behaviors is not known. OBJECTIVES: The objective of the study was to evaluate the association between early-life adversity and circulating the levels of the adipomyokines such as leptin, adiponectin, and irisin and the inflammatory marker, C-reactive protein (CRP). DESIGN/SUBJECTS/SETTING: This study was a cross-sectional study of 95 adults at a university-based research center. We collected venous blood from participants and analyzed serum for leptin, adiponectin, irisin, and CRP. RESULTS: Circulating leptin, irisin, and CRP levels were significantly higher in the highest adversity tertile group compared with low and middle tertile groups (P < .001 for leptin, P = .01 for irisin, and P = .02 for CRP). Adiponectin levels were lower in the highest tertile group compared with the low and middle tertile groups (P = .03). After adjusting for demographic variables, physical activity, diet, current mental health, and body mass index, the associations between early-life adversity leptin, irisin, and did not change. However, adiponectin and CRP levels were no longer significantly related to early life adversity. CONCLUSION: Early-life adversity is directly associated with elevated circulating leptin and irisin, and indirectly associated with elevated CRP and decreased adiponectin. These findings suggest that these adipomyokines may play a role in the pathogenesis of metabolic abnormality in a population with significant early life adversity.

Detailed assessments of childhood adversity enhance prediction of central obesity independent of gender, race, adult psychosocial risk and health behaviors.

OBJECTIVE: This study examined whether a novel indicator of overall childhood adversity, incorporating number of adversities, severity, and chronicity, predicted central obesity beyond contributions of "modifiable" risk factors including psychosocial characteristics and health behaviors in a diverse sample of midlife adults. The study also examined whether the overall adversity score (number of adversities × severity × chronicity) better predicted obesity compared to cumulative adversity (number of adversities), a more traditional assessment of childhood adversity. MATERIALS/METHODS: 210 Black/African Americans and White/European Americans, mean age=45.8; ±3.3 years, were studied cross-sectionally. Regression analysis examined overall childhood adversity as a direct, non-modifiable risk factor for central obesity (waist-hip ratio) and body mass index (BMI), with and without adjustment for established adult psychosocial risk factors (education, employment, social functioning) and heath behavior risk factors (smoking, drinking, diet, exercise). RESULTS: Overall childhood adversity was an independent significant predictor of central obesity, and the relations between psychosocial and health risk factors and central obesity were not significant when overall adversity was in the model. Overall adversity was not a statistically significant predictor of BMI. CONCLUSIONS: Overall childhood adversity, incorporating severity and chronicity and cumulative scores, predicts central obesity beyond more contemporaneous risk factors often considered modifiable. This is consistent with early dysregulation of metabolic functioning. Findings can inform practitioners interested in the impact of childhood adversity and personalizing treatment approaches of obesity within high-risk populations. Prevention/intervention research is necessary to discover and address the underlying causes and impact of childhood adversity on metabolic functioning.

Gender dimorphism and lack of day/night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans.

OBJECTIVE: Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. DESIGN AND METHODS: Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. RESULTS: Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. CONCLUSIONS: The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported.

Circulating irisin in relation to insulin resistance and the metabolic syndrome.

CONTEXT: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown. OBJECTIVE: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk. DESIGN, SETTING, AND SUBJECTS: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects. RESULTS: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = -0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes. CONCLUSIONS: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.

Induction of mucosal HIV-specific B and T cell responses after oral immunization with live coxsackievirus B4 recombinants.

Given the limited success of clinical HIV vaccine trials, new vaccine strategies are needed for the HIV pipeline. The present study explored the novel concept that a live enteric virus, with limited disease potential, is a suitable vaccine vector to elicit HIV-specific immune responses in the gut mucosa of immunized mice. Two coxsackievirus B4 (CVB4) vaccine vectors were designed to induce HIV-specific B or T cell responses. A B cell immunogen, CVB4/gp41(2F5), was constructed by expressing an epitope from the membrane proximal external region (MPER) of gp41 as a structural peptide within a surface loop of a capsid protein of CVB4. The T cell immunogen, CVB4/p24(73(3)), was constructed previously by expressing a gag p24 sequence as a non-structural peptide at the amino-terminus of the CVB4 polyprotein. The CVB4/gp41(2F5) recombinant was antigenic in mice and elicited anti-gp41 antibodies in both the mucosal and systemic compartments. The route of immunization affected the antibody response since oral delivery of CVB4/gp41(2F5) induced anti-gp41 antibodies in the mucosal but not in the systemic compartment while parenteral delivery induced anti-gp41 antibodies in both compartments. In contrast, oral immunization with CVB4/p24(73(3)) elicited both mucosal and systemic gag p24-specific T cell responses. Since coxsackieviruses are ubiquitous in the human population, a key question is whether pre-existing vector immunity will inhibit the ability of a CVB4-based vaccine to induce HIV-specific immune responses. We show that pre-existing vector immunity did not preclude the development of mucosal anti-gp41 antibodies or gag p24-specific T cell responses after oral immunization with the CVB4/HIV recombinants. We suggest that the CVB4/HIV recombinants have the potential to be a viable vaccine product because of ease of delivery, safety, immunogenicity, ease of large-scale production, and storage conditions requiring cold-chain temperatures provided by refrigeration.