Publications

NF-κB Activation in Hypothalamic Pro-opiomelanocortin Neurons Is Essential in Illness- and Leptin-induced Anorexia

Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-kappaB (NF-kappaB), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-kappaB. In vitro, NF-kappaB activation directly stimulated the transcriptional activity of pro-opiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-kappaB in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-kappaB and melanocortin. Furthermore, disruption of I kappaB kinase-beta, an upstream kinase of NF-kappaB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-kappaB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-kappaB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-kappaB also serves as a downstream signaling pathway of leptin.

The role of parental support in the prediction of youth physical activity behaviour

Interrupting Sitting Time in Postmenopausal Women: Protocol for the Rise for Health Randomized Controlled Trial

Background Many older adults spend the majority of their waking hours sitting, which increases their risk of chronic diseases. Given the challenges that many older adults face when engaging in moderate-to-vigorous physical activity, understanding the health benefits of decreasing sitting time and increasing the number of sit-to-stand transitions is needed to address this growing public health concern. Objective The aim of this 3-arm randomized controlled trial is to investigate how changes in sitting time and brief sit-to-stand transitions impact biomarkers of healthy aging and physical, emotional, and cognitive functioning compared with a healthy attention control arm. Methods Sedentary and postmenopausal women (N=405) will be recruited and randomly assigned to 1 of the 3 study conditions for 3 months: healthy living attention control (Healthy Living), reduce sitting time (Reduce Sitting), and increase sit-to-stand transitions (Increase Transitions). Assessments conducted at baseline and 3 months included fasting blood draw, blood pressure, anthropometric measurements, physical functioning, cognitive testing, and 7 days of a thigh-worn accelerometer (activPAL) and a hip-worn accelerometer (ActiGraph). Blood-based biomarkers of healthy aging included those associated with glycemic control (glycated hemoglobin, fasting plasma insulin and glucose, and homeostatic model assessment of insulin resistance). Results Recruitment began in May 2018. The intervention is ongoing, with data collection expected to continue through the end of 2022. Conclusions The Rise for Health study is designed to test whether 2 different approaches to interrupting sitting time can improve healthy aging in postmenopausal women. Results from this study may inform the development of sedentary behavior guidelines and interventions to reduce sitting time in older adults. Trial Registration ClinicalTrials.gov NCT03473145; https://clinicaltrials.gov/ct2/show/NCT03473145 International Registered Report Identifier (IRRID) DERR1-10.2196/28684

p38α Inhibits Liver Fibrogenesis and Consequent Hepatocarcinogenesis by Curtailing Accumulation of Reactive Oxygen Species

Most hepatocellular carcinomas (HCC) develop in the context of severe liver fibrosis and cirrhosis caused by chronic liver inflammation, which also results in accumulation of reactive oxygen species (ROS). In this study, we examined whether the stress-activated protein kinase p38α (Mapk14) controls ROS metabolism and development of fibrosis and cancer in mice given thioacetamide to induce chronic liver injury. Liver-specific p38α ablation was found to enhance ROS accumulation, which appears to be exerted through the reduced expression of antioxidant protein HSP25 (Hspb1), a mouse homolog of HSP27. Its reexpression in p38α-deficient liver prevents ROS accumulation and thioacetamide-induced fibrosis. p38α deficiency increased expression of SOX2, a marker for cancer stem cells and the liver oncoproteins c-Jun (Jun) and Gankyrin (Psmd10) and led to enhanced thioacetamide-induced hepatocarcinogenesis. The upregulation of SOX2 and c-Jun was prevented by administration of the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with ROS accumulation in liver. Thus, p38α and its target HSP25/HSP27 appear to play a conserved and critical hepatoprotective function by curtailing ROS accumulation in liver parenchymal cells engaged in oxidative metabolism of exogenous chemicals. Augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis.

Abstract IA04: Metabolic control of HCC initiation and progression

Abstract Non-alcoholic steatohepatitis (NASH) is quickly becoming the leading HCC etiology. NASH can lead to HCC by altering liver metabolism, inducing oncogenic mutations, causing tumor promoting inflammation as well as the immunosuppression of anti-HCC immunity. We have established an accurate model for studying NASH-induced HCC development, the MUP-uPA mouse, and used it to show that elevated TNF production by liver macrophages contributes to both NASH and HCC progression. The major cause of TNF induction during NASH is gut-derived endotoxin, whose infiltration into the portal circulation is enhanced by barrier disrupting diets that are high in fats or fructose. By disrupting autophagy and activating NF-kB, HFD feeding of MUP-uPA mice results in accumulation of p62, the major constituent of Mallory-Denk bodies, within hepatocytes. Accumulation of p62 is not required for induction of hepatosteatosis but it greatly accelerates and enhances NASH to HCC progression through the activation of NRF2 and mTORC1. Conditional activation of NRF2 in hepatocytes results in hepatomegaly due to induction of EGF and PDGF family members as well as altered liver metabolism, in part by triggering the degradation of fructose-1,6 bisphosphate phosphatase (FBP1). FBP1 is rate limiting for gluconeogenesis and its germ-line inherited deficiency results in a complex metabolic disorder that includes hypoglycemia, lactic acidosis, hepatomegaly, hepatosteatosis, hyperlipidemia and liver damage and is manifested only in response to glucose starvation. By generating Fbp1ΔHep mice, we found that FBP1 has enzymatic and non-enzymatic activities, the latter of which are due to formation of a multiprotein complex with aldolase B (ALDOB) and PP2A-C that interacts with AKT, dephosphorylates it and inhibits its activation. By inhibiting AKT activation, FBP1 and ALDOB suppress HCC development. Citation Format: Michael Karin, Li Gu, Yahui Zhu. Metabolic control of HCC initiation and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA04.

Bicycling to university: evaluation of a bicycle-sharing program in Spain

This study examined the change in behavioral stages (e.g. contemplation, action and maintenance) of cycling to university before and after the implementation of a new public bicycle share program (PBSP) and promotion of its use. The study also determined the change in the prevalence, correlates of PBSP use and potential role in the promotion of healthy weight. An 8-month follow-up cross-sectional study (September 2010–April 2011) was carried out among undergraduate students during the first season of implementation of the PBSP in Valencia, Spain. The sample was 173 students (68.2% female) with a mean age of 21.3 years (SD 3.06) who attended a PBSP promotional session. The data were collected by questionnaire. Results indicated a significant increase of 14.6% in the action/maintenance stage of change and showed that 19% of the participants were PBSP users 8 months later. The behavioral stage did not change when students always had access to car/motorbike, lived further than 5 km from the university and had no bicycle stations within 250 m from home. Those most likely to start using PBSP were students who were in the contemplation stage, perceived fewer environmental and safety barriers to active commuting and had one or more stations within 250 m of home. PBSP users expended ∼257 metabolic equivalent·minutes/week bicycling to university, and there was a small reduction in BMI. Findings suggest that PBSPs can be considered as useful promoters of cycling behavior and may contribute to weight control in university students.

Tracking the Road from Inflammation to Cancer: the Critical Role of IκB Kinase (IKK)

Ocular relaxation to reduce eye movements

Cognitive activities influence the rate and direction of eye movements, but the effect of various levels of eye activity on cognition has not been tested.

The development of a data model for research on the environmental correlates of physical inactivity and obesity.

Development of information systems to support research on environmental correlates of physical activity and nutrition has to date been largely ad hoc and driven by single research project requirements. In this rapidly growing field, research databases are becoming increasingly complex as researchers attempt to model the impact of multiple aspects of the environment such as neighborhood characteristics, site and building design, and nutritional environments on both aggregate and individual level measures of physical activity and weight. The presentation reports on the initial implementation of a logical data model in the context of an ongoing research program that is exploring the relation of neighborhood physical and demographic characteristics on physical activity levels measured in time and space.

INTERRELATIONSHIPS BETWEEN HEALTH RISK BEHAVIORS AND PHYSICAL ACTIVITY IN COLLEGE SENIORS 85

The interrelationship among health behaviors are not clearly understood. We examined health risk behaviors and their relationship to various types of physical activity in an ethnically diverse group of 576 men and women (mean age 24.5±2 yr) at a large urban university. Measures of risk behaviors were obtained by questionnaire, while physical activity was assessed by telephone interview using the Blair Seven Day Recall. Hierarchical multiple regressions were conducted to determine whether health risk behaviors of men and women were associated with physical activity after adjusting for potential demographic confounders, including ethnic status, marital status or employment status. Nineteen risk behavior items were factor analyzed, yielding five risk behavior factors, including tobacco use, drinking and driving, eating fatty foods, lack of healthy foods, and unsafe sex risk scales for men and for women. For men, the regression analyses demonstrated a relationship between physical activity and eating healthy foods (r=0.24, p<0.05), but no association with other risk behaviors, nor was there a relationship between demographic confounders and physical activity. For women, total energy expenditure was related to eating fewer fatty foods (r=0.15), while engaging in vigorous physical activity was associated with eating more healthy foods(r=0.14). Unmarried women were more likely to engage in physical activity than married women (r=0.13), but this finding was not present for men. In addition, European American women participated in more vigorous physical activity than did all other ethnic groups (r=0.13, p<0.01). Physical activity was not strongly related to other health behaviors in this sample of college seniors. Further examination of these relationships is needed to help health promotion professionals design interventions for specific populations.

AP-1 Repressor Protein JDP-2: Inhibition of UV-Mediated Apoptosis through p53 Down-Regulation

Members of the AP-1 transcription factor family, especially c-Jun and c-Fos, have long been known to mediate critical steps in the cellular response to ultraviolet (UV) irradiation. We sought to examine whether two newly discovered members of the AP-1 family, JDP-1 and JDP-2, also participate in the mammalian UV response. Here we report that JDP-2, but not JDP-1, is transiently induced upon UV challenge and that elevated levels of JDP-2 increase cell survival following UV exposure. This protective function of JDP-2 appears to be mediated through repression of p53 expression at the transcriptional level, via a conserved atypical AP-1 site in the p53 promoter.

Tracking dietary intake in white and Mexican-American children from age 4 to 12 years

Objective To examine the tracking (ie, the stability over time) of dietary intake in Mexican-American and white children aged 4 to 12 years. Subjects Children 4 years of age (n=351) were assessed at baseline and 65% (n=228) completed the 8-year study. Design Cardiovascular disease-related dietary intake was defined as energy, percent of energy from fat, and sodium (mg/1,000 kcal). From age 4 to 7 years, a modified 24-hour recall with observation of lunch and dinner and interview of the primary food preparer for unobserved foods was used to describe dietary intake. For children aged 11 to 12 years, a standardized 24-hour recall was used. Statistical Analyses A mixed effects model that adjusted for sex, ethnicity, and measurement wave allowed for separation of shorter-term variations in diet from more stable (“between subject”) variations. Extent of between-subject variance is an indication of tracking. Results From age 4 to age 7, there were statistically significant between-subject variance components for energy (P<.00001), percent of energy from fat (P<.00001), and sodium per 1,000 kcals (P<.001); for ages 11 and 12, energy intake was significant (P<.00001). There were no significant associations for dietary intake from age 4 to 12 years. Conclusions/Applications It seems that dietary intakes are stable over short periods and at earlier ages compared with longer intervals and later ages. Nutrition interventions are needed in childhood and throughout adolescence. J Am Diet Assoc. 2002;102:683–689.

Validation of a Physical Activity Self-Report Questionnaire in a Portuguese Pediatric Population

The goal of this study was to validate an adapted version of the “weekly checklist” in a Portuguese population. The validity was assessed by comparing self-reports against the Computer Science and Application, Inc (CSA) monitor. The sample comprised 109 children (boys, n = 42; girls, n = 67), aged 8 to 16 years old. All subjects were volunteers from local schools (Oporto region). The weekly activity checklist was modestly ( r = 0.30) but significantly ( p &lt; .01) correlated with the CSA. Girls ( r = 40; p &lt; .01) had higher correlations than boys (0.28; p &lt; .05). When the values were analyzed by age, excluding the young subjects (&lt;10 years old), the correlation values were slightly higher ( r = 0.38; p &lt; .01). The Portuguese version of the “weekly activity checklist” had similar reliability and validity as the original version. The measure appears to have lower validity in 8- and 9-year-old children.

Reliability and validity of a fruit and vegetable screening measure for adolescents

We developed and evaluated a brief measure of fruit and vegetable consumption for adolescents. The measure was reliable and significantly correlated with 3-day food record data. Correct classification rate (63%) and specificity (63%) were good. Sensitivity (33%) was lower. The measure is recommended, although improvements in classification are still needed.

Interrupting Sitting Time in Postmenopausal Women: Protocol for the Rise for Health Randomized Controlled Trial (Preprint)

<sec> <title>BACKGROUND</title> Many older adults spend the majority of their waking hours sitting, which increases their risk of chronic diseases. Given the challenges that many older adults face when engaging in moderate-to-vigorous physical activity, understanding the health benefits of decreasing sitting time and increasing the number of sit-to-stand transitions is needed to address this growing public health concern. </sec> <sec> <title>OBJECTIVE</title> The aim of this 3-arm randomized controlled trial is to investigate how changes in sitting time and brief sit-to-stand transitions impact biomarkers of healthy aging and physical, emotional, and cognitive functioning compared with a healthy attention control arm. </sec> <sec> <title>METHODS</title> Sedentary and postmenopausal women (N=405) will be recruited and randomly assigned to 1 of the 3 study conditions for 3 months: healthy living attention control (Healthy Living), reduce sitting time (Reduce Sitting), and increase sit-to-stand transitions (Increase Transitions). Assessments conducted at baseline and 3 months included fasting blood draw, blood pressure, anthropometric measurements, physical functioning, cognitive testing, and 7 days of a thigh-worn accelerometer (activPAL) and a hip-worn accelerometer (ActiGraph). Blood-based biomarkers of healthy aging included those associated with glycemic control (glycated hemoglobin, fasting plasma insulin and glucose, and homeostatic model assessment of insulin resistance). </sec> <sec> <title>RESULTS</title> Recruitment began in May 2018. The intervention is ongoing, with data collection expected to continue through the end of 2022. </sec> <sec> <title>CONCLUSIONS</title> The Rise for Health study is designed to test whether 2 different approaches to interrupting sitting time can improve healthy aging in postmenopausal women. Results from this study may inform the development of sedentary behavior guidelines and interventions to reduce sitting time in older adults. </sec> <sec> <title>CLINICALTRIAL</title> ClinicalTrials.gov NCT03473145; https://clinicaltrials.gov/ct2/show/NCT03473145 </sec> <sec> <title>INTERNATIONAL REGISTERED REPORT</title> DERR1-10.2196/28684 </sec>

The development of scales to measure social support for diet and exercise behaviors

THE GROWTH HORMONE GENE FAMILY: STRUCTURE, EVOLUTION, EXPRESSION, AND REGULATION11This work was supported by NIH Grants AM19997 and AM18878 and NSF Grant 8004735.

C-Jun Nh2-Terminal Kinase (Jnk)1 and Jnk2 Have Similar and Stage-Dependent Roles in Regulating T Cell Apoptosis and Proliferation

Apoptotic and mitogenic stimuli activate c-Jun NH2-terminal kinases (JNKs) in T cells. Although T cells express both JNK1 and JNK2 isozymes, the absence of JNK2 alone can result in resistance to anti-CD3-induced thymocyte apoptosis and defective mature T cell proliferation. Similar defects in thymocyte apoptosis and mature T cell proliferation, the latter due to reduced interleukin 2 production, are also caused by JNK1 deficiency. Importantly, T cell function was compromised in Jnk1(+/-)Jnk2(+/-) double heterozygous mice, indicating that JNK1 and JNK2 play similar roles in regulating T cell function. The reduced JNK dose results in defective c-Jun NH2-terminal phosphorylation in thymocytes but not in peripheral T cells, in which nuclear factors of activated T cells (NK-ATs)-DNA binding activity is affected. Thus, JNK1 and JNK2 control similar functions during T cell maturation through differential targeting of distinct substrates.