Psychiatry and Behavioral Sciences Publications

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Crisis Outreach, Treatment Engagement, and Outcomes after Suicide Risk Screenings in a Comprehensive Mental Health Platform
(2025-08-29) Graupensperger, Scott; Hawrilenko, Matt; Brown, Millard; Baum, Graham; Ward, Emily J.; Chekroud, Adam
Objective: To evaluate the short- and long-term outcomes of proactive crisis outreach within 24 hours of a suicidal ideation (SI) flag. Outcomes assessed via 6 months of follow-up data included treatment engagement indices and symptom trajectories (SI, depression, anxiety) following an SI flag. Methods: Real-world data were drawn from 6,131 individuals aged 15 years or older enrolled in a comprehensive mental health platform (Spring Health) who flagged for SI and had not engaged in treatment in the prior 6 months (Mage=35.4, SD=11.5; 51.5% women). The primary exposure was successful care navigator contact within 24 hours of the SI event. Results: Of the 6,131 participants with SI, 93.3% attended at least one therapy or medication management appointment within 6-months of SI flag. Successful crisis outreach was associated with greater odds of treatment initiation (OR=2.37 [1.99, 2.82]), 33% shorter time to first appointment (time ratio=0.67 [0.63, 0.72]), and greater odds of early care retention (OR=1.69 [1.51, 1.89]). Mediation analyses supported time to care as a key pathway linking outreach to both early retention and total utilization. Even after adjusting for treatment engagement, crisis contact was associated with 30% lower odds of SI recurrence (OR=0.70 [0.61, 0.80]) and steeper reductions in SI, depressive, and anxiety symptoms that were maintained over time. Conclusions: Timely outreach following an SI screen was associated with improved treatment access, sustained treatment engagement, and symptom reduction. Results support tech-enabled crisis outreach within a comprehensive mental health platform as a scalable strategy for early suicide intervention and care continuity.
All my friends are doing it: Perceived social norms predict heavier sports betting behavior among young adults
(2025-02-07) Lambuth, Joseph; Shaygan, Arvin; Lostutter, Ty W.; Graupensperger, Scott
Background. Sports betting is the fastest growing gambling behavior, particularly among young adults. Despite burgeoning evidence of the public health concerns associated with sports betting, antecedents of this addictive behavior are largely understudied. Informed by seminal psychological theories of conformity and existing norms-based prevention paradigms for high-risk behavior, the current study aimed to examine perceived social norms as a potential explanatory factor for sports betting behavior. Method. The sample was comprised of 221 young adults from 36 different US states (Mage=24.4; 77.7% male; 64.6% white). Eligibility criteria included betting on sports at least twice in the past month. At baseline, participants reported perceptions of friends’ approval and engagement in sports betting, and then two weeks later reported indices of their own sports betting behavior. Results. Generally, young adults perceived their peers to wager much more on sports betting than they themselves reported wagering, suggesting potential normative misperceptions. Those who perceived their friends to be more accepting of, and more engaged in sports betting, reported engaging in more sports betting behaviors in the subsequent two-week period. Injunctive norms more strongly predicted young adults’ total number of bets, whereas descriptive norms more strongly predicted total amount wagered and negative consequences. Conclusion. Findings provide foundational evidence for peer influence processes on sports betting behaviors among young adults. These key early-stage findings inform how social norms, and other psychosocial factors, may be leveraged within forthcoming prevention/intervention approaches aimed at stymieing the rapidly growing harms associated with sports betting.
More than Fun and Games: Problematic Sports Betting and Its Adverse Impact on Mental Health and Well-Being in Young Adults
(2024-08-30) Shaygan, Arvin; Lambuth, Joseph; Song, Frank; Hurtado, Modesto; Song, Frank
Background: The rapid rise in sports betting, especially among young adults (age 18-29), necessitates identifying health correlates of this addictive behavior. The present study examined associations between sports betting and mental health and well-being, which represents a timely literature gap. Method: The sample was 221 young adult sport bettors from 36 different states (M¬age = 24.4, 77.7% male). Regression models estimated associations between problem sports betting severity (PGSI-SB) and symptoms of depression, anxiety, psychological distress, loneliness, and stress, as well as indices of well-being, including satisfaction with life, optimism, connectedness, and social functioning. Results: Findings reveal robust associations between problem sports betting severity and each index of mental health symptomology, and inverse associations with indices of well-being. The strongest relative effect size was the association between problem sports betting severity and stress (a 1SD increase in PGSI-SB score corresponded to 48% of a standard deviation increase in stress). Conclusions: This study provides novel and timely evidence for associations between problem sports betting and various indices of mental health and well-being; thus, highlighting the need for more research on this topic and the rapid development of prevention/intervention strategies aimed at the intersection of sports betting and mental health.
Beyond fear of side effects: Distrust and perceived need of COVID-19 vaccinations are salient drivers of vaccine intentions in young adults with prolonged non-adoption
(2024-07-05) Graupensperger, Scott; Ilar, Amaris
Reducing vaccine hesitancy is a critical public health priority, but it remains unclear which specific beliefs most strongly drive vaccine hesitancy. The present study compared strength of associations between several hesitant beliefs and vaccine intentions among a diverse sample of 546 young adults (Mage=21.7, representing 45 different states in the US) with prolonged non-adoption of COVID-19 vaccination (i.e., all participants were still unvaccinated several years into the pandemic). Fear of side effects and beliefs about vaccine effectiveness were not strongly associated with vaccine intentions, but distrust of COVID-19 vaccines and believing that one does not need a COVID-19 vaccine were the strongest relative predictors of vaccine intentions (i.e., inverse associations). Thus, findings highlight the need to improve trust of public health institutions and increase perceived need for vaccination as potential target points for increasing vaccine uptake among young adults with prolonged non-adoption, even beyond the COVID-19 vaccine.
Are online norms-based alcohol interventions efficacious for college students with higher social anxiety?
(2024-06-03) Walukevich-Dienst, Katherine; Graupensperger, Scott; Piccirillo, Marilyn L.; Smith-LeCavalier, Kirstyn N.; Acolin, Jessica; Larimer, Mary E.
Undergraduates with higher social anxiety are at greater risk for co-occurring substance misuse, heavier drinking in certain contexts, and more negative alcohol-related consequences. Among undergraduates, alcohol-focused online norms-based interventions provide consistent and cost-effective reductions in alcohol use and related risks. However, research on norms-based interventions for undergraduates with higher social anxiety symptoms is limited, and less is known about the longitudinal impacts of social anxiety symptoms on the efficacy of online, norms-based alcohol interventions.
Sports Betting and Hazardous Alcohol Use among Young Adults: Added Risks of Betting and Drinking on the Same Day
(2024-04-27) Graupensperger, Scott; Song, Frank; Lambuth, Joseph; Shaygan, Arvin; Hurtado, Modesta; Lostutter, Ty W.
Background. Sports betting is growing in popularity at alarming rates, especially among young adults. However, sports betting is not yet widely considered as a public health concern due in part to scarce examination of health correlates. The present study entailed cross-sectional examination of associations between problem sports betting and indices of hazardous alcohol use and negative alcohol-related consequences, and whether associations were moderated by same-day drinking and sports betting. Method. The sample comprised 221 young adults aged 18-29 with representation from 36 different states in the U.S. (Mage=24.4; 77.7% male; 64.6% white). Eligibility criteria included betting on sports at least twice in the past month. Results. Zero truncated hurdle models revealed that problem sports betting scores were significantly associated with hazardous alcohol use (i.e., AUDIT scores) for those who drank at least once in the past 3-months. Problem sports betting was also associated with any (vs. no) negative alcohol-related consequences, as well as the number of negative consequences young adults experienced. Both count models were moderated by same-day drinking and sports betting such that positive associations were amplified among those who more frequently drank and bet on sports on the same day. Conclusions. Findings provide early-stage evidence for a link between problem sports betting and alcohol-related problems among young adults, especially among those who more frequently engage in both behaviors within the same timeframe. These results highlight the need for more research on sports betting from a public health lens as the prevalence of this addictive behavior continues to rise.
Validation of a Sports Betting Adaptation to the Problem Gambling Severity Index in Young Adults
(2024-04-18) Graupensperger, Scott; Calhoun, Brian
Background. Sports betting is a rapidly growing addictive behavior, especially among young adults. As such, there is a need for measuring problem sports betting behaviors and consequences separately from established generalized gambling measures. The present study provides support for a sports betting adaptation of the Problem Gambling Severity Index (PGSI-SB). Methods. We recruited a sample (N=221) of young adults aged 18-29 (Mage=24.4; 22% female; 13.2% Hispanic; 68.6% college degree) from 36 different US states. Eligibility criteria included ≥2 sports betting days in the past month. Results. Confirmatory factor analyses showed support for both a single and two-factor model with subscales for problematic behavior (e.g., dependence) and negative consequences. The PGSI-SB was strongly correlated with the original PGSI in terms of scale-level and item-level correlations (i.e., convergent validity). Aim 3 established predictive validity of the single-factor PGSI-SB via significant associations with three indices of past two-week sports betting: frequency, number of bets, and total amount wagered. Predictive validity for the two-factor model was impacted by multicollinearity, given high correlation between subscales. Conclusions. Findings establish the merits of a dedicated problem sports betting measure for young adults, which is a key step towards enhancing the quality and consistency of sports betting research.
Alcohol Use Disorder as a Moderator in the Relationship Between PTSD and Suicidality Among Military Personnel
(2023-11-09) Walton, Thomas O.; Graupensperger, Scott; Walker, Denise D.; Kaysen, Debra;
Background: Alcohol use disorder (AUD), posttraumatic stress disorder (PTSD), and suicide are substantial public health concerns among military service members, yet the nature of their relationships is not well understood. The present study tests the hypothesis that AUD moderates the relationship between PTSD symptom severity and suicidality. Methods: This secondary analysis uses data collected at baseline for a randomized clinical trial. The sample consists of 161 active-duty service members from three service branches (Army, Air Force, and Navy). All participants met diagnostic criteria for PTSD and were not engaged in evidence-based PTSD treatment at the time of enrollment. Zero-inflated Poisson generalized linear regression models were used to test the associations of PTSD and AUD symptom severity with likelihood and severity of suicidal ideation. Results: Findings suggest that AUD symptom severity moderates (i.e., amplifies) the relationship between PTSD symptoms and severity of suicidal ideation among military personnel with untreated PTSD. Among service members with low or absent AUD, no significant association was found between PTSD symptoms and severity of suicidal ideation. However, when AUD severity was average (i.e., sample mean) or high, PTSD symptoms had a significant positive association with severity of suicidal ideation. Conclusions: This study highlights the importance of including assessment of AUD and PTSD in suicide risk evaluations. Further, results provide strong support for the maintenance and further development of treatment programs that simultaneously address AUD and PTSD comorbidity in the military health system.
Protocol Design for Utilizing Daily Assessments to Examine Daily Level Predictors of Impaired Driving Behaviors in Young Adults
(2021-11-17) Hultgren, Brittney
Background: Motor vehicle crashes remain a leading cause of death among young adults (ages 18–25) in the United States. Many drivers implicated in these crashes are under the influence of alcohol, cannabis, or the simultaneous use of alcohol and cannabis. Extremely limited research has assessed impaired driving behaviors and their predictors at the daily level. Perceived norms and motives to use substances have empirical support suggesting they may impact impaired driving-related behavior. Novel approaches to assess these associations at the daily level are needed and may inform future intervention and prevention programs. Objective: The goal of the current study is to utilize electronic daily assessments to assess driving under the influence of alcohol, cannabis, or simultaneous use and riding with a driver impaired by these substances to assess variability and predictors of these impaired driving-related behaviors at the daily level. This present manuscript details a protocol, measures, and a plan of analyses to assess how within-person differences in perceived norms and motives to use are associated with the likelihood of engaging in impaired driving-related behaviors. Methods: Participants include young adults in Washington State who report simultaneous use in the past month and either driving under the influence of alcohol, cannabis, or simultaneous use, or riding with a driver under the influence of both substances in the past 6 months. Individuals who verify their identity and meet eligibility requirements will complete a baseline assessment after which they will be scheduled for training on the daily assessment procedure via Zoom. Next, they will be invited to complete daily surveys on Thursday, Friday, Saturday, and Sunday every other week for 6 months and a 6-month follow up assessment. Analyses will utilize multilevel models with days nested within individuals. Results: The study is currently recruiting participants. A total of 98 participants have been recruited and 16 have completed daily assessments. Data collection is expected to be completed in Summer 2022. Conclusions: This study utilizes a novel design to assess impaired driving and predictors at the daily level among young adults at high risk of impaired driving-related behaviors. Findings will provide unique data that will shape the knowledge base in the field of social science and public health substance use research and that may be helpful for future prevention and intervention efforts on impaired driving.
Hypopituitarism caused by blast-related mTBI may result in PTSD-like symptoms
(Society for Behavioral Neuroendocrinology, 2017-06-11) Schultz, Jaclyn S.; Burges, Debra E.; Shofer, Jane B; Wilkinson, Charles W.
Recent studies in civilian populations have found the prevalence of hypopituitarism as a result of head injuries from all causes to be between 25 and 50%. However, the neuroendocrine effects of concussion, or mild traumatic brain injury (mTBI) due to explosive blasts have received relatively little attention. Blast-related mTBI is the most common injury sustained by U.S. troops deployed to Iraq or Afghanistan. Approximately 20% of returning service members have experienced one or more blast-related concussions. Posttraumatic hypopituitarism (PTHP) has been shown to result in several symptoms that overlap considerably with those of PTSD. These include fatigue, depression, sexual dysfunction, anxiety, social isolation, and detrimental effects on sleep, learning and memory, body composition, and quality of life. We are investigating the prevalence of PTHP in two groups of Veterans of deployment to Iraq or Afghanistan. Members of the TBI group sustained at least one blast-related mTBI; members of the deployment control (DC) group experienced similar extreme conditions but did not experience a blast concussion. We conducted screening for growth hormone deficiency (GHD), hypogonadism, thyroid deficiency, and secondary adrenal insufficiency (sAI) by measuring basal blood samples and by testing for GHD and sAI with the glucagon stimulation test. Eighteen of 44 (36.4%) TBI group participants and seven of 32 (15.6%) DC group participants screened positive for pituitary hormone deficits. GHD and sAI were observed most frequently. We used behavioral self-reports and cognitive testing to examine symptom prevalence. Veterans with TBI and pituitary dysfunction endorsed more severe and/or frequent symptoms than those in the TBI group without hypopituitarism or the DC group. These findings and observations suggest that screening for pituitary dysfunction after head injuries holds promise for not only recognizing appropriate treatment options that might not otherwise be considered, but also facilitating recovery and rehabilitation of these service members.
DOPA Decarboxylase Modulates Tau Toxicity
(Elsevier, 2018-03-01) Kow, Rebecca L.; Sikkema, Carl; Wheeler, Jeanna M.; Wilkinson, Charles W.; Kraemer, Brian C.
BACKGROUND: The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. METHODS: To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene–induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. RESULTS: We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. CONCLUSIONS: Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.
High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury
(Frontiers in Neurology, 2012-02-07) Wilkinson, Charles W.; Pagulayan, Kathleen F.; Petrie, Eric C.; Mayer, Cynthia L.; Colasurdo, Elizabeth A.; Shofer, Jane B.; Hart, Kim L.; Hoff, David; Tarabochia, Matthew A.; Peskind, Elaine R.
Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25–50% ofcases. Most studies found the occurrence of post traumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.
The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia
(Am J Physiol Endocrinol Metab., 2008-05) Sanders, Nicole M.; Wilkinson, Charles W.; Taborsky Jr., Gerald J.; Al-Noori, Salwa; Daumen, Wendi; Zavosh, Aryana; Figlewicz, Dianne P.
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with comorbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRR to single or recurrent hypoglycemia in nondiabetic rats. Since there are time-dependent effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6- or 20-day sertraline treatment on hypoglycemia CRR. We found that 6-day sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle (VEH)-treated rats (t = 120: VEH, 2,573 ± 448 vs. SERT, 4,202 ± 545 pg/ml, P < 0.05). In response to recurrent hypoglycemia, VEH-treated rats exhibited the expected impairment in epinephrine secretion (t = 60: 678 ± 73 pg/ml) vs. VEH-treated rats experiencing firsttime hypoglycemia (t = 60: 2,081 ± 436 pg/ml, P < 0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t = 60: 1,794 ± 276 pgl/ml). In 20-day SERTtreated rats, epinephrine, norepinephrine, and glucagon CRR were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similarly to 6-day SERT treatment, 20-day SERT treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6- nor 20-day sertraline treatment impaired hormonal CRR to hypoglycemia in nondiabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRR and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats.
Reduced Anorexigenic Efficacy of Leptin, But Not of the Melanocortin Receptor Agonist Melanotan-II, Predicts Diet- Induced Obesity in Rats
(Endocrinology, 2005-12) van Dijk, Gertjan; de Vries, Koert; Nyakas, Csaba; Buwalde, Bauke; Adage, Tiziana; Kuipers, Folkert; Kas, Martien J.H.; Adan, Roger A.H.; Wilkinson, Charles W.; Thiele, Todd E.; Scheurink, Anton J.W.
Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in out-bred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle4,D-Phe7]α-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin’s anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.
Physiological regulation of hypothalamic IL-1 gene expression by leptin and glucocorticoids: implications for energy homeostasis
(Am J Physiol Endocrinol Metab, 2004-08) Wisse, Brent E.; Ogimoto, Kayoko; Morton, Gregory J.; Wilkinson, Charlew W.; Frayo, R.Scott; Cummings, David E.; Schwartz, Michael W.
Physiological regulation of hypothalamic IL-1 gene expression by leptin and glucocorticoids: implications for energy homeostasis. Am J Physiol Endocrinol Metab 287: E1107–E1113, 2004. First published August 10, 2004; doi:10.1152/ajpendo.00038. 2004.—Interleukin-1 (IL-1 ) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1 gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1 mRNA levels twofold, measured by real-time PCR (P 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1 mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation (P 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1 mRNA levels in fa/fa rats (P 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1 mRNA levels by 30% (P 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1 gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1 mRNA levels twofold (P 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1 is subject to
Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat
(American Psychological Society, 1999) Van Dijk, Gertjan; Seely, Randy J.; Thiele, Todd E.; Friedman, Mark I.; Ji, Hong; Wilkinson, Charles W.; Burn, Paul; Campfield, Arthur; Tenenbauim, Renata; Raskin, Denis G.; Woods, Stephen C.
Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat. Am. J. Physiol. 276 (Regulatory Integrative Comp. Physiol. 45): R1425–R1433, 1999.—To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 μg) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (28%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (215%) and gastrointestinal fill (250%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin’s anorexigenic action.
Low Plasma Leptin Levels Contribute to Diabetic Hyperphagia in Rats
(Diabetes, 1999-06) Sindelar, Dana K.; Havel, Peter J.; Seeley, Randy J.; Wilkinson, Charlew W.; Woods, Stephen C.; Schwartz, Michael W.
The adipocyte hormone leptin reduces food intake in normal animals. During uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake increases. To test the hypothesis that low leptin levels contribute to diabetic hyperphagia, we investigated the e ffect on food intake of replacement of leptin at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled diabetes induced by streptozotocin (STZ). One group of STZ diabetic rats received saline (STZ + Sal) (n = 11), while the other group (STZ + Lep) (n = 15) received a subcutaneous infusion of recombinant rat leptin (100 μg ? k g– 1 ? d a y– 1) via osmotic minipumps. A nondiabetic control group (Con) (n = 11) received saline only. In the STZ + Sal group, plasma leptin levels decreased by 75% (P < 0.05) from 2.4 ± 0.5 on the day before STZ/citrate buffer vehicle ( Veh) injection (day 0) to 0.6 ± 0.2 ng/ml on day 7. In contrast, plasma leptin levels on days 3–7 were comparable to pretreatment values in both the STZ + Lep group (day 0: 2.6 ± 0.4 vs. day 7: 2.5 ± 0.3 ng/ml, NS) and the Con group (day 0: 3.8 ± 0.4 vs. day 7: 2.9 ± 1.0 ng/ml, NS). In the STZ + Sal group, daily food intake increased gradually to values 43% above basal by day 7 (day 0: 24 ± 2 to day 7: 33 ± 3 g, P < 0.05), whereas food intake did not increase in either the STZ + Lep group (day 0: 24 ± 1 vs. day 7: 21 ± 2 g, NS), or the Con group (day 0: 23 ± 1 vs. day 7: 23 ± 2 g). Plasma glucose levels exceeded nondiabetic control values (7.7 ± 0.2 mmol/l) in both diabetic groups, but were lower in the STZ + Lep group (17.2 ± 1.8 mmol/l) than in the STZ + Sal group (24.3 ± 1.1 mmol/l, P < 0.05). To determine if sensitivity to leptin-induced anorexia was affected by STZ treatment, a second experiment was performed in which the effect of intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 μg) on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed both 4- and 24-h food intake in the two groups to an equal extent at every dose (by 15, 22, and 35%, respectively). These findings support the hypothesis that the effect of uncontrolled diabetes to lower leptin levels contributes to diabetic hyperphagia and that this effect is not due to altered leptin sensitivity. D i a b e t e s 48:1275–1280, 1999
Hypothalamic Melanin-Concentrating Hormone and Estrogen- Induced Weight Loss
(Journal of Neuroscience, 2000-11-15) Mystkowski, Paul; Seely, Randy J.; Hahn, Tina M.; Baskin, Denis G.; Havel, Peter J.; Matsumoto, Alvin M.; Wilkinson, Charles W.; Peacock-Kinzig, Kimberly; Blake, Kathleen A.; Schwartz, Michael W.
Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.
Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study
(The Journal of Clinical Endocrinology & Metabolism, 2001) Wilkinson, Charles W.; Petrie, Eric C.; Murray, Sharon R.; Colasudro, Elizabeth A.; Raskind, Murray R.; Peskind, Elaine R.
We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20–35 yr, n 5 22) and old (.65 yr, n 5 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids. (J Clin Endocrinol Metab 86: 545–550, 2001)
Glucocorticoid Induction of the Glaucoma Gene MYOC in Human and Monkey Trabecular Meshwork Cells and Tissues
(Investigative Ophthalmology & Visual Science,, 2001-07) Clark, Abbot F.; Steely, Thomas; Dickerson Jr., Jaime E.; English-Wright, Sherry; Stropki, Karen; McCartney, Mitchell D.; Jaconson, Nasreen; Shepard, Allan R.; Clark, John I.; Matsushima, Hiroyuki; Peskind, Elaine R.; Leverenz, James B.; Wilkinson, Charles W.; Swiderski, Ruth E.; Fingert, John H.; Sheffield, Val C.; Stone, Edwin M.
PURPOSE. To examine the intracellular and extracellular expression of myocilin in the human and primate trabecular meshwork (TM) in the presence and absence of glucocorticoids. METHODS. Myocilin expression was examined in cultured human TM cells by Northern blot analysis and myocilin antibody– mediated immunoprecipitation. Myocilin expression was quantified using high-resolution two-dimensional polyacrylamide gel electrophoresis of radiolabeled proteins from human TM cells, TM tissue explants, and perfused human anterior segments cultured with and without dexamethasone (DEX) for 14 to 21 days, as well as TM tissue from pigtailed monkeys treated orally for 1 year with cortisone acetate. Immunofluorescence with anti-myocilin antibodies was used to localize cellular and extracellular expression of myocilin in cultured human TM cells. RESULTS. Glucocorticoid treatment caused a significant induction of myocilin mRNA, a tetrad of cell-associated proteins, and 8 to 20 secreted proteins (molecular mass [Mr] 56 and 59 kDa and isoelectric point [pI] 5.2 and 5.3) in some, but not all the cultured human TM cells and explanted tissues. Western immunoblot analysis using anti-myocilin peptide antibodies identified these proteins as encoded by the MYOC gene. There was significant induction of the myocilin proteins in three perfusion- cultured human eyes, in which DEX-induced elevated intraocular pressure developed. Monkeys treated 1 year with cortisol acetate showed steroid glaucoma-like morphologic changes in the TM that correlated with the induction of myocilin in the TM. Immunofluorescence analysis of cultured TM cells localized myocilin intracellularly in discrete perinuclear and cytoplasmic vesicular deposits as well as extracellularly on the cell surface associated with the extracellular matrix. In several DEX-treated TM cell lines, there were significant levels of myocilin secreted into the media. Enzymatic deglycosylation of proteins in the TM media converted the higher molecular weight isoforms of myocilin (;57 kDa) to the lower molecular weight isoforms (;55 kDa). CONCLUSIONS. Although the function of myocilin is unknown, induction of these TM proteins was found in eyes in which glucocorticoid-induced ocular hypertension developed. Therefore, myocilin may play an important pathogenic role in ocular hypertension in addition to its role in certain forms of POAG. (Invest Ophthalmol Vis Sci. 2001;42:1769–1780)

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