Prioritizing a research agenda on built environments and physical activity: a twin panel Delphi consensus process with researchers and knowledge users.

BACKGROUND: The growth of urban dwelling populations globally has led to rapid increases of research and policy initiatives addressing associations between the built environment and physical activity (PA). Given this rapid proliferation, it is important to identify priority areas and research questions for moving the field forward. The objective of this study was to identify and compare research priorities on the built environment and PA among researchers and knowledge users (e.g., policy makers, practitioners). METHODS: Between September 2022 and April 2023, a three-round, modified Delphi survey was conducted among two independent panels of international researchers (n = 38) and knowledge users (n = 23) to identify similarities and differences in perceived research priorities on the built environment and PA and generate twin 'top 10' lists of the most important research needs. RESULTS: From a broad range of self-identified issues, both panels ranked in common the most pressing research priorities including stronger study designs such as natural experiments, research that examines inequalities and inequities, establishing the cost effectiveness of interventions, safety and injuries related to engagement in active transportation (AT), and considerations for climate change and climate adaptation. Additional priorities identified by researchers included: implementation science, research that incorporates Indigenous perspectives, land-use policies, built environments that support active aging, and participatory research. Additional priorities identified by knowledge users included: built environments and PA among people living with disabilities and a need for national data on trip chaining, multi-modal travel, and non-work or school-related AT. CONCLUSIONS: Five common research priorities between the two groups emerged, including (1) to better understand causality, (2) interactions with the natural environment, (3) economic evaluations, (4) social disparities, and (5) preventable AT-related injuries. The findings may help set directions for future research, interdisciplinary and intersectoral collaborations, and funding opportunities.

Scoping review of adult-oriented outdoor play publications in Canada. / Examen de la portée des publications sur le jeu à l'extérieur chez les adultes au Canada.

INTRODUCTION: Since 2015, there has been growing interest in Canada and beyond on the benefits of outdoor play for physical, emotional, social and environmental health, wellbeing and development, for adults as well as children and youth. METHODS: This scoping review aims to answer the question, "How, and in what context, is adult-oriented outdoor play being studied in Canada?" We conducted an electronic search for peer-reviewed articles on outdoor play published in English or French after September 2015 by authors from Canadian institutions or about Canadian adults. The 224 retrieved articles were organized according to eight priorities: health, well-being and development; outdoor play environments; safety and outdoor play; cross-sectoral connections; equity, diversity and inclusion; professional development; Indigenous Peoples and land-based outdoor play; and COVID-19. We tallied the study designs and measurement methods used. RESULTS: The most common priority was outdoor play environments; the least common were COVID-19 and Indigenous Peoples and land-based outdoor play. Cross-sectional studies were the most common; no rapid reviews were identified. Sample sizes varied from one auto-ethnographic reflection to 147 000 zoo visitor datapoints. More studies used subjective than objective measurement methods. Environmental health was the most common outcome and mental/emotional development was the least. CONCLUSION: There has been a staggering amount of articles published on adult-oriented outdoor play in Canada since 2015. Knowledge gaps remain in the relationship between outdoor play and adult mental/emotional development; the connections between environmental health and Indigenous cultures and traditions; and how to balance promoting outdoor unstructured play with protecting and preserving natural spaces.

Scoping review of children's and youth's outdoor play publications in Canada. / Examen de la portée des publications sur le jeu à l'extérieur chez les enfants et les jeunes au Canada.

INTRODUCTION: Since 2015, interest in the benefits of outdoor play for physical, emotional, social and environmental health, well-being and development has been growing in Canada and elsewhere. METHODS: This scoping review aims to answer the question, "How, and in what context, is children's and youth's outdoor play being studied in Canada?" Included were studies of any type on outdoor play published after September 2015 in English or French by authors from Canadian institutions or assessing Canadian children and/or youth. Articles retrieved from MEDLINE, CINAHL and Scopus by March 2021 were organized according to eight priority areas: health, well-being and development; outdoor play environments; safety and outdoor play; cross-sectoral connections; equity, diversity and inclusion; professional development; Indigenous Peoples and land-based outdoor play; and COVID-19. Within each priority, study design and measurement method were tallied. RESULTS: Of the 275 articles included, the most common priority area was health, wellbeing and development (n = 239). The least common priority areas were COVID-19 (n = 9) and Indigenous Peoples and land-based outdoor play (n = 14). Cross-sectional studies were the most common; the least common were rapid reviews. Sample sizes varied from one parent's reflections to 999 951 data points from health databases. More studies used subjective than objective measurement methods. Across priorities, physical health was the most examined outcome, and mental/emotional development the least. CONCLUSION: A wealth of knowledge on outdoor play in Canada has been produced since 2015. Further research is needed on the relationship between outdoor play and mental/emotional development among children and youth.

Play, Learn, and Teach Outdoors-Network (PLaTO-Net): terminology, taxonomy, and ontology.

BACKGROUND: A recent dialogue in the field of play, learn, and teach outdoors (referred to as "PLaTO" hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the field evolves and diversifies in its approaches, contents, and contexts over time and in different countries, cultures, and settings. Within this paper, we report the systematic and iterative processes undertaken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). METHODS: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and definitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then finalized based on the feedback received from 50 international PLaTO member participants who responded to ≥ 3 rounds of the consultation survey and dialogue. Finally, efforts to share and disseminate project outcomes were made through different online platforms. RESULTS: This paper presents the final definitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontology model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The final terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). CONCLUSIONS: This project contributes to advancing PLaTO-based research and facilitating intersectoral and interdisciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO's synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO.

Regional differences in movement behaviours of children and youth during the second wave of the COVID-19 pandemic in Canada: follow-up from a national study.

OBJECTIVES: Public health restrictions varied by region during the COVID-19 pandemic and reduced opportunities for children to be physically active. The purpose of this study was to assess regional differences in movement behaviours of Canadian children and youth during the second wave of the COVID-19 pandemic. METHODS: A national sample of Canadian parents (n=1568; 58% women) of children and youth (5-17 years of age) completed an online survey. Participants were classified based on region of residence (British Columbia, Prairies, Ontario, Quebec, or Atlantic Canada). Differences in movement and play behaviours (physical activity, outdoor play, sleep, screen time) between children and youth living in different regions were examined. RESULTS: Compared to children and youth in Quebec (the region with the highest COVID-19 prevalence), children and youth in the Prairies (F(1,1563)=9.0, p=0.01) and Atlantic Canada (F(1,1563)=17.1, p<0.001) participated in more moderate-to-vigorous physical activity (MVPA). Compared to Quebec, living in Atlantic Canada increased the odds of meeting the MVPA guideline (odds ratio (OR)=2.1, p=0.02), living in Ontario decreased the odds of meeting the sleep guideline (OR=0.6, p=0.01), and living in Ontario (OR=0.7, p=0.04) or Atlantic Canada (OR=0.6, p=0.049) decreased the odds of meeting the screen time guideline. Children and youth in Atlantic Canada demonstrated smaller declines in outdoor play than their counterparts in Quebec. CONCLUSION: Movement and play behaviours varied between regions of Canada where the highest COVID-19 prevalence corresponded to lower odds of meeting the physical activity guidelines. Low compliance with 24-hour movement guidelines suggests that regional pandemic recovery plans need to prioritize opportunities for healthy movement.

RéSUMé: OBJECTIFS: Les restrictions sanitaires ont varié d'une région à l'autre durant la pandémie de COVID-19, et elles ont réduit les possibilités pour les enfants d'être actifs. Notre étude visait à évaluer les différences régionales dans les comportements liés au mouvement des enfants et des jeunes canadiens au cours de la deuxième vague de la pandémie. MéTHODE: Un échantillon national de parents canadiens (n = 1 568; 58 % de femmes) d'enfants et de jeunes (5­17 ans) ont répondu à un sondage en ligne. Les participants ont été classés selon leur région de résidence (Colombie-Britannique, Prairies, Ontario, Québec ou Canada atlantique). Les différences dans les comportements liés au mouvement et au jeu (activité physique, jeu à l'extérieur, sommeil, temps d'écran) entre les enfants et les jeunes de différentes régions ont été examinées. RéSULTATS: Comparativement aux enfants et aux jeunes du Québec (la région qui présentait la plus forte prévalence de COVID-19), les enfants et les jeunes des Prairies (F(1,1563) = 9,0, p = 0,01) et du Canada atlantique (F(1,1563) = 17,1, p < 0,001) ont fait plus d'activité physique modérée à vigoureuse (APMV). Comparativement au Québec, le fait de vivre au Canada atlantique a accru la probabilité de respecter les lignes directrices sur l'APMV (rapport de cotes (RC) = 2,1, p = 0,02), le fait de vivre en Ontario a réduit la probabilité de respecter les lignes directrices sur le sommeil (RC = 0,6, p = 0,01), et le fait de vivre en Ontario (RC = 0,7, p = 0,04) ou au Canada atlantique (RC = 0,6, p = 0,049) a réduit la probabilité de respecter les lignes directrices sur le temps d'écran. Les enfants et les jeunes du Canada atlantique ont présenté des baisses moins importantes du jeu à l'extérieur que les enfants et les jeunes du Québec. CONCLUSION: Les comportements liés au mouvement et au jeu ont varié d'une région à l'autre du Canada; là où la prévalence de la COVID-19 était la plus élevée, la probabilité de respecter les lignes directrices sur l'activité physique était la plus faible. La faible conformité aux lignes directrices sur le mouvement sur une période de 24 heures donne à penser que les plans de rétablissement régionaux après la pandémie devront accorder la priorité aux possibilités de mouvement sain.

Physical activity, diet, and weight loss in patients recruited from primary care settings: An update on obesity management interventions.

BACKGROUND: Obesity and related comorbidities are the most common chronic conditions in North America where behavior modification including the adoption of physical activity (PA) and a healthful diet are primary treatment strategies. Patients are more likely to engage in behavior modification if encouraged by their physician; however, behavioral counseling in primary care rarely occurs due to lack of training and resources. A more effective method may be to refer patients from clinical settings to other health professionals. OBJECTIVE: This systematic review examines the effectiveness of behavior-based counseling for obesity management among participants referred from clinical settings. METHODS: PubMed, CINAHL, and EMBASE were used to identify randomized clinical trials (2014-2020) for weight loss with the following inclusion criteria: trial duration ≥12 months, included a control or usual care group, recruited adults with overweight or obesity from primary care and/or treated in the primary care setting, and the intervention included counseling on PA and diet. RESULTS: Seventeen studies, encompassing 21 different intervention groups with 6185 unique participants (56% female) met the inclusion criteria. All participants had overweight or obesity, with a body mass index between 28.2 and 41.0 kg/m2. In 11 (52%) of the intervention groups, significant weight loss in the intervention group was observed compared to usual care (mean weight loss: 4.9[2.1] kg vs. 1.0[0.9] kg). In 13 out of 18 interventions (72%) reporting weight loss at two time points, weight regain was observed by 12 months. Statistically significant weight loss was observed in one intervention (of two total) that was longer than 12 months. CONCLUSIONS: Sustained weight loss regardless of the behavior-based, intervention strategy remains a challenge for most adults. Given the established benefits of routine PA and a healthful diet, prioritizing the adoption of healthy behaviors regardless of weight loss may be a more effective strategy for ensuring long-term health benefit.

Regional differences in access to the outdoors and outdoor play of Canadian children and youth during the COVID-19 outbreak.

To reduce the spread of COVID-19, public health authorities across the country have recommended that Canadians keep their distance, wash their hands, and stay home. To enforce these measures, restrictions on outdoor behaviour have been implemented, limiting access to parks and recreational outdoor spaces. New evidence shows that COVID-19 restrictions are associated with an overall lower amount of time spent in outdoor play among Canadian children and youth. This is concerning, as outdoor play is important for children's physical and mental health and helps provide them with a sense of control during times of uncertainty and stress. As policies on access to the outdoors during the COVID-19 outbreak vary by province, it is possible that policy differences have led to regional differences in changes in outdoor play among children and youth. In this commentary, we examine regional differences in outdoor play among children and youth across Canada, and the association between provincial policies related to COVID-19 and outdoor play. We argue that through the recovery process, in the event of a second wave of infections, and in preparing for future public health challenges, policy decisions should consider ways to preserve outdoor play for Canadian children and youth.

RéSUMé: Pour réduire la propagation de la COVID-19, les autorités de santé publique du pays ont recommandé aux Canadiens de garder leurs distances, de se laver les mains et de rester chez eux. Pour faire respecter ces mesures, des restrictions ont été appliquées aux comportements en plein air en limitant l'accès aux parcs et aux espaces récréatifs à l'extérieur. De nouvelles données probantes montrent que les restrictions en lien avec la COVID-19 sont associées à une baisse générale du temps consacré au jeu à l'extérieur par les enfants et les jeunes du Canada. C'est préoccupant, car le jeu à l'extérieur est important pour leur santé physique et mentale et leur donne un sentiment de contrôle en période d'incertitude et de stress. Comme les politiques d'accès à l'extérieur durant l'éclosion de COVID-19 varient d'une province à l'autre, il est possible que différentes politiques aient donné lieu à des écarts régionaux dans l'évolution du jeu à l'extérieur chez les enfants et les jeunes. Dans notre commentaire, nous examinons les différences régionales du jeu à l'extérieur chez les enfants et les jeunes au Canada et l'association entre les politiques provinciales liées à la COVID-19 et le jeu à l'extérieur. Nous faisons valoir que tant durant le processus de reprise qu'en cas de seconde vague d'infections et en prévision des futurs problèmes de santé publique, les décisions stratégiques devraient songer aux moyens de préserver le jeu à l'extérieur pour les enfants et les jeunes du Canada.

Nonexercise Equations for Determining Change in Cardiorespiratory Fitness.

PURPOSE: This study aimed to determine whether change in estimated cardiorespiratory fitness (eCRF) is associated with change in measured cardiorespiratory fitness (mCRF) independent of exercise amount and intensity over 24 wk. METHODS: Participants were 163 sedentary adults with abdominal obesity (mean ± SD waist circumference, 109.9 ± 11.5 cm) randomly assigned to (i) no-exercise control (n = 42); (ii) low-amount, low-intensity exercise (LALI; n = 39); (iii) high-amount, low-intensity exercise (HALI; n = 51); and (iv) high-amount, high-intensity exercise (HAHI; n = 31). mCRF was measured using a maximal treadmill test at baseline, 8, 16, and 24 wk. eCRF was calculated using a published nonexercise equation with the following variables: sex, age, waist circumference, resting heart rate, and self-selected physical activity. RESULTS: Participants attended 115 of 120 exercise sessions prescribed (96.0% ± 4.0% adherence). eCRF change from baseline to 8, 16, and 24 wk was not different from mCRF change for control, LALI, or HALI (P = 0.03). In HAHI, eCRF change was significantly greater than mCRF change at all time points (P < 0.001). Further analysis revealed that change in eCRF systematically overestimated and underestimated small and large changes in mCRF, respectively, in all groups (P < 0.001). CONCLUSIONS: eCRF change was associated with mCRF change at 24 wk independent of exercise amount but not intensity. Systematic variation between eCRF and mCRF highlights a possible limitation when using eCRF to follow change in mCRF, specifically that eCRF does not capture the individual variability of the mCRF response.

Change in Submaximal Cardiorespiratory Fitness and All-Cause Mortality.

OBJECTIVE: To evaluate the relationship between change in submaximal cardiorespiratory fitness (sCRF) and all-cause mortality risk in adult men and women. PATIENTS AND METHODS: A prospective study with at least 2 clinical visits (mean follow-up time, 4.2±3.0 years) between April 1974 and January 2002 was conducted to assess the relationship between change in sCRF and mortality risk during follow-up. Participants were 6106 men and women. Submaximal CRF was determined using the heart rate obtained at the 5-minute mark of a graded maximal treadmill test used to determine maximal CRF (mCRF). Change in sCRF from baseline to follow-up was categorized into 3 groups: increased fitness (decreased heart rate, <-4.0 beats/min), stable fitness (heart rate, -4.0 to 3.0 beats/min), and decreased fitness (increased heart rate, >3.0 beats/min). RESULTS: The mean change in sCRF at follow-up for all 6106 study participants was -0.5±10.0 beats/min, and the mean change in mCRF was -0.3±1.4 metabolic equivalents. Change in sCRF was related to change in mCRF, though the variance explained was small (R2=0.21; P<.001). The hazard ratios (95% CIs) for all-cause mortality were 0.60 (0.38-0.96) for stable and 0.59 (0.35-1.00) for increased sCRF compared with decreased sCRF after adjusting for age, change in weight, and other common risk factors for premature mortality. The hazard ratios for changes in sCRF and mCRF were not significant after adjusting for changes in mCRF (P=.29) and sCRF (P=.60), respectively. CONCLUSION: A simple 5-minute submaximal test of CRF identified that adults who maintained or improved sCRF were less likely to die from all causes during follow-up than were adults whose sCRF decreased.

Effects of intensity and amount of exercise on measures of insulin and glucose: Analysis of inter-individual variability.

AIM: To determine the separate effects of exercise amount and intensity on the rate of response for glucose and insulin variables, where rate of response was defined as the number of individuals with improvement in glucose and insulin values that was beyond the day-to-day variability of measurement. METHODS: Participants were 171 sedentary, middle-aged abdominally obese adults who completed a 24-week intervention. Participants were randomly assigned to (1) no-exercise control (n = 51), (2) low-amount, low-intensity exercise (LALI, n = 38), (3) high-amount, low-intensity exercise (HALI, n = 52), or (4) high-amount, high-intensity exercise (HAHI, n = 30). Two-hour glucose, insulin area under the curve (AUC), and fasting insulin were measured during a 2-hour, 75g oral glucose challenge. The day-to-day variability for these measures was calculated to be ±2.2 mmol/L, ±940.2 pmol/L, and ±38.9 pmol/L, respectively. RESULTS: At 24 weeks, the number of nonresponders for 2-hr glucose was 98.0%, 86.8%, 94.2%, 86.7% in the control, LALI, HALI, and HAHI groups, respectively. The number of nonresponders for insulin AUC was 88.0%, 75.7%, 75.0%, 80.0% in the control, LALI, HALI, and HAHI groups, respectively. The number of nonresponders for fasting insulin was 88.2%, 84.2%, 84.6%, 93.3% in the control, LALI, HALI, and HAHI groups, respectively. The rate of response was not different between control and any of the exercise groups for any measure (p>0.05). CONCLUSION: The improvement in glucose and insulin measures did not exceed the day-to-day variability of measurement for approximately 80% of the participants independent of exercise amount or intensity.

Comparison of Measures of Maximal and Submaximal Fitness in Response to Exercise.

INTRODUCTION: Adoption of physical activity (PA) consistent with current guidelines does not improve maximal cardiorespiratory fitness (mCRF; V˙O2peak) beyond the error of measurement for approximately 30% of adults. Whether PA improves measures of exercise tolerance at submaximal levels (submaximal cardiorespiratory fitness [sCRF]) independent of change in mCRF is unknown. Here we assessed the relationship between exercise-induced changes in mCRF and sCRF. METHODS: Twenty-five physically inactive men 30-60 yrs old (mean ± SD = 44.3 ± 9.1 yr) completed 4 wk of supervised exercise consisting of 30 min of exercise, five times per week at 65% mCRF. mCRF was assessed using a maximal treadmill test. sCRF was measured as follows: 1) exercise tolerance, the distance traveled during a 12-min time trial on a treadmill, and 2) change in heart rate (HR) at submaximal work rates during the maximal treadmill test. Daily PA was measured by accelerometry at baseline and 4 wk. RESULTS: mCRF (P = 0.009) and both measures of sCRF (P < 0.001) improved at 4 wk. No change in measures of daily PA was observed at 4-wk compared with baseline (P > 0.05). No association was observed between exercise-induced change in mCRF and change in either measure of sCRF (P > 0.05) after exercise training. In the group of participants who did not improve mCRF beyond the measurement error (n = 13, or 52%), we observed a significant improvement in both measures of sCRF (P < 0.001). Among these 13 individuals, all improved in at least one measure of sCRF. CONCLUSION: Exercise-induced improvements in mCRF were not associated with improvements in either measure of sCRF. Improvements in submaximal measures of cardiorespiratory fitness are observed in the absence of change in mCRF. Measures of sCRF capture peripheral adaptations to exercise not captured by measures of mCRF alone.

Separate Effects of Intensity and Amount of Exercise on Interindividual Cardiorespiratory Fitness Response.

OBJECTIVE: To determine the separate effects of exercise intensity and amount on interindividual cardiorespiratory fitness (CRF) response. PARTICIPANTS AND METHODS: Participants were 121 (75 females, 62%) sedentary, middle-aged (mean [SD] age, 53.2 [7.5] years), abdominally obese adults who completed at least 90% of 5 weekly exercise sessions prescribed over a 24-week intervention. Participants were randomly assigned to (1) low-amount, low-intensity exercise (LALI) (180 and 300 kcal per session for women and men, respectively, at 50% of CRF [VO 2peak]; n=39), (2) high-amount, low-intensity exercise (HALI) (360 and 600 kcal per session for women and men, respectively, at 50% of CRF; n=51), or high-amount, high-intensity exercise (HAHI) (360 and 600 kcal per session for women and men, respectively, at 75% of CRF; n=31). Cardiorespiratory fitness was measured using a treadmill test at 4, 8, 16, and 24 weeks. The study duration was September 1, 2009, through May 31, 2013. RESULTS: Cardiorespiratory fitness increased within all 3 groups at 24 weeks (P<.001). At 24 weeks, 38.5% (15 of 39), 17.6% (9 of 51), and 0% (0 of 31) of the participants within the LALI, HALI, and HAHI groups, respectively, were CRF nonresponders. At a fixed exercise intensity, increasing exercise amount reduced the rate of nonresponse by 50% (P=.02). At a fixed amount of exercise, increasing the exercise intensity eliminated nonresponse (P=.001). Exposure to exercise decreased the number of CRF nonresponders between 4 and 8 weeks for LALI and by 16 weeks for HALI but plateaued thereafter. For HAHI, the number of CRF nonresponders decreased continually over the 24 weeks. CONCLUSION: For a fixed amount of exercise, increasing exercise intensity consistent with consensus recommendations eliminated CRF nonresponse. Low-intensity exercise may not be sufficient to improve CRF for a substantial proportion of sedentary obese adults.

Changing the endpoints for determining effective obesity management.

Health authorities worldwide recommend weight loss as a primary endpoint for effective obesity management. Despite a growing public awareness of the importance of weight loss and the spending of billions of dollars by Americans in attempts to lose weight, obesity prevalence continues to rise. In this report we argue that effective obesity management in today's environment will require a shift in focus from weight loss as the primary endpoint, to improvements in the causal behaviors; diet and exercise/physical activity (PA). We reason that increases in PA combined with a balanced diet are associated with improvement in many of the intermediate risk factors including cardiorespiratory fitness (CRF) associated with obesity despite minimal or no weight loss. Consistent with this notion, we suggest that a focus on healthy behaviors for the prevention of additional weight gain may be an effective way of managing obesity in the short term.

Evolution and phylogeny of the corticotropin-releasing factor (CRF) family of peptides: expansion and specialization in the vertebrates.

New sequence data on CRF family members from a number of genomes has led to the modification of our understanding of CRF evolution in the Metazoa. The corticotropin-releasing factor (CRF) family of peptides include four paralogous lineages in jawed vertebrates; CRF, urotensin-I/urocortin/sauvagine, urocortin 2 (Ucn2) and urocortin 3 (Ucn3). CRF and the urotensin-I/urocortin/sauvagine group represent a gene duplication from one lineage, whereas Ucns 2 and 3 are the result of a gene duplication in the other paralogous lineage. Both paralogous lineages are the result of a gene duplication from a single ancestral peptide that occurred after the divergence of the tunicates from the ancestor that led to the evolution of chordates and vertebrates. The presence of a single CRF-like peptide in tunicates and insects suggests that a single CRF-like ancestor was present before the separation of deuterostomes and protostomes. Currently there is no strong evidence that indicates that CRF-like peptides were present in metazoan taxa that evolved before this time although the structural similarity between some CRF peptides in insects, tunicates and vertebrates with the calcitonin family of peptides hints that prior to the formation of deuterostomes and protostomes the ancestral peptide possessed both CRF and calcitonin-like structural attributes. Here, we show evidences of conservation of CRF-like function dating back to early prokaryotes. This ancestral CRF-calcitonin-like peptide may have initially resulted from a horizontal gene transfer event from prokaryotes to a protistan species that later gave rise to the metazoans.

Origin of chordate peptides by horizontal protozoan gene transfer in early metazoans and protists: evolution of the teneurin C-terminal associated peptides (TCAP).

The teneurin C-terminal associated peptides (TCAP) are found at the extracellular face in C-terminal region of the teneurin transmembrane proteins. One of these peptides, TCAP-1 is independently transcribed as a smaller bioactive peptide that possesses a number of stress response-attenuating activities. The teneurin-TCAP system appears to be the result of a horizontal gene transfer from a prokaryotic proteinaceous polymorphic toxin to a choanoflagellate. In a basal metazoan, the TCAP region has been modified from a toxin to a soluble intercellular signaling system. New studies indicate that the teneurin-TCAP system form a complex signaling system associated with adhesion, cytoskeletal regulation and intracellular signaling. TCAP-1 is highly conserved in all vertebrates and in mammals, inhibits corticotropin-releasing factor (CRF)-associated stress. Using the TCAP-teneurin system as a model, it is likely that numerous peptide systems in the Chordata began as a result of horizontal gene transfer from prokaryotes early in metazoan ancestry.

C-terminal processing of the teneurin proteins: independent actions of a teneurin C-terminal associated peptide in hippocampal cells.

Many neuropsychiatric conditions have a common set of neurological substrates associated with the integration of sensorimotor processing. The teneurins are a recently described family of proteins that play a significant role in visual and auditory development. Encoded on the terminal exon of the teneurin genes is a family of bioactive peptides, termed teneurin C-terminal associated peptides (TCAP), which regulate mood-disorder associated behaviors. Thus, the teneurin-TCAP system could represent a novel neurological system underlying the origins of a number of complex neuropsychiatric conditions. However, it is not known if TCAP-1 exerts its effects as part of a direct teneurin function, whereby TCAP represents a functional region of the larger teneurin protein, or if it has an independent role, either as a splice variant or post-translational proteolytic cleavage product of teneurin. In this study, we show that TCAP-1 can be transcribed as a smaller mRNA transcript. After translation, further processing yields a smaller 15 kDa protein containing the TCAP-1 region. In the mouse hippocampus, immunoreactive (ir) TCAP-1 is exclusively localized to the pyramidal layers of the CA1, CA2 and CA3 regions. Although the localization of TCAP and teneurin in hippocampal regions is similar, they are distinct within the cell as most ir-teneurin is found at the plasma membrane, whereas ir-TCAP-1 is predominantly found in the cytosol. Moreover, in mouse embryonic hippocampal cell culture, FITC-labeled TCAP-1 binds to the plasma membrane and is taken up into the cytosol via dynamin-dependent caveolae-mediated endocytosis. Our data provides novel evidence that TCAP-1 is structurally and functionally distinct from the larger teneurins.

Modulation of neuroplastic changes and corticotropin-releasing factor-associated behavior by a phylogenetically ancient and conserved peptide family.

The co-evolution of peptides and early cells some 3.7 billion years ago provided bioactive peptides with a long history for the proliferation and refinement of peptide hormones. Central to the adaptation and evolution of cell types in metazoans is the development of peptide signaling systems that regulate stress mechanisms. The corticotropin-releasing factor (CRF) family of peptides represents the canonical family of peptides that are pivotal to the regulation of stress in vertebrates. However, these peptides appear to have evolved at least 2 billion years after the formation of the first postulated bioactive peptides, suggesting that before this, other peptide systems played a role in stress and energy metabolism. The teneurin C-terminal associated peptides (TCAPs) are a recently discovered family of highly conserved peptides that are processed from the teneurin transmembrane proteins. This peptide/protein system is ubiquitous in multicellular organisms and evolved before the CRF family. TCAP-1 is a potent regulator of CRF-associated physiology and behavior and may play a significant role in the regulation of cell-to-cell communication and neuroplasticity in neurons.