Fuel metabolism in Canada geese: effects of glucagon on glucose kinetics.

During prolonged fasting, birds must rely on glucose mobilization to maintain normoglycemia. Glucagon is known to modulate avian energy metabolism during prolonged fasting, but the metabolic effects of this hormone on long-distance migrant birds have never been investigated. Our goal was to determine whether glucagon regulates the mobilization of the main lipid and carbohydrate fuels in migrant birds. Using the Canada goose (Branta canadensis) as a model species, we looked for evidence of fuel mobilization via changes in metabolite concentrations. No changes could be found for any lipid fraction, but glucagon elicited a strong increase in glucose concentration. Therefore, we aimed to quantify the effects of this hormone on glucose kinetics using continuous infusion of 6-[(3)H]-d-glucose. Glucagon was found to cause a 50% increase in glucose mobilization (from 22.2 ± 2.4 µmol·kg(-1)·min(-1) to 33.5 ± 3.3 µmol·kg(-1)·min(-1)) and, together with an unchanged rate of carbohydrate oxidation, led to a 90% increase in plasma glucose concentration. This hormone also led to a twofold increase in plasma lactate concentration. No changes in plasma lipid concentration or composition were observed. This study is the first to demonstrate how glucagon modulates glucose kinetics in a long-distance migrant bird and to quantify its rates of glucose mobilization.

Residential trajectories of street youth-the Montréal Cohort Study.

Little is known about the course of homelessness among youth between the ages of 18 and 25 despite the many characteristics distinguishing them from adolescents and from older street-involved populations. We examined the residential trajectories of homeless young adults in Montréal over a 21-month period and identified determinants of various trajectory profiles. The 365 study participants (79 % men, mean age 21.9 years) were followed for an average of 515 days (range 81-630 days). We assessed housing status with a questionnaire based on the residential follow-back calendar designed by the New Hampshire Dartmouth Research Center. Using latent growth analysis to examine achievement of residential stability over time, we observed three different trajectories: group 1 presented a low probability of housing throughout the entire study period; group 2 showed a high probability of early and stable housing; group 3 displayed a fluctuating pattern. Protective correlates of residential stability included high school education, birth in Canada, and presence of mental health problems. Drug abuse or dependence was associated with a decreased probability of housing.

Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Residential trajectory and HIV high-risk behaviors among Montréal street youth--a reciprocal relationship.

Evidence has linked residential instability and engagement in high-risk behaviors. This paper longitudinally examines the relationship between changes in residential stability and changes in HIV risk behaviors among Montréal street youth (SY). Between April 2006 and May 2007, 419 SY (18-25 years old) were recruited in a cohort study. SY (using Montréal street youth agencies services) were eligible if they had had at least one 24-hour episode of homelessness in the previous 30 days. Baseline and follow-up interviews, carried out every 3 months, included completion of a questionnaire (based on Life History Calendar Technique) assessing daily sleeping arrangements since the last interview, and monthly sexual and drug use behaviors. Using mixed-effects logistic regression method, we examined the association between various risk behaviors and residential stability, reached when a youth resided in any of the following settings for a whole month: own place; friends'/partner's/parent's place; any types of housing service (excluding emergency shelters). Analyses were carried out controlling for gender, age, education level, lifetime duration of homelessness, childhood sexual trauma, and lifetime mental health disorders. As of January 2009, 360 SY (79% boys) had completed at least one follow-up interview, representing 4,889 months of follow-up. Residential stability was significantly associated with the following: sex exchange (adjusted odd ratio [AOR], 0.25; 95% confidence interval [CI], 0.14-0.37), drug injection (AOR, 0.55; CI, 0.33-0.76), daily alcohol consumption (AOR, 0.58; CI, 0.42-0.74), polydrug consumption (AOR, 0.61; CI, 0.50-0.73), polydrug consumption excluding marijuana (AOR, 0.55; CI, 0.45-0.65), and multiple sex partners (≥3 partners; AOR, 0.57; CI, 0.40-0.74). Our results suggest a reciprocal relationship between residential instability and HIV risk behaviors. This calls for more integrated services combining both individual and structural-level interventions to improve the health of street youth.

Fuel selection in Wistar rats exposed to cold: shivering thermogenesis diverts fatty acids from re-esterification to oxidation.

This study characterizes the effects of shivering thermogenesis on metabolic fuel selection in Wistar rats. Because lipids account for most of the heat produced, we have investigated: (1) whether the rate of appearance of non-esterified fatty acids (R(a) NEFAs) is stimulated by shivering, (2) whether mono-unsaturated (oleate) and saturated fatty acids (palmitate) are affected similarly, and (3) whether the partitioning between fatty acid oxidation and re-esterification is altered by cold exposure. Fuel oxidation was measured by indirect calorimetry and fatty acid mobilization by continuous infusion of 9,10-[(3)H]oleate and 1-[(14)C]palmitate. During steady-state cold exposure, results show that total heat production is unequally shared by the oxidation of lipids (52% of metabolic rate), carbohydrates (35%) and proteins (13%), and that the same fuel selection pattern is observed at all shivering intensities. All previous research shows that mammals stimulate R(a) NEFA to support exercise or shivering. In contrast, results reveal that the R(a) NEFA of the rat remains constant during cold exposure (55 micromol kg(1) min(1)). No preferential use of mono-unsaturated over saturated fatty acids could be demonstrated. The rat decreases its rate of fatty acid re-esterification from 48.4 +/- 6.4 to 19.6 +/- 6.3 micromol kg(1) min(1) to provide energy to shivering muscles. This study is the first to show that mammals do not only increase fatty acid availability for oxidation by stimulating R(a) NEFA. Reallocation of fatty acids from re-esterification to oxidation is a novel, alternative strategy used by the rat to support shivering.

Randomized controlled trial of motivational interviewing for reducing injection risk behaviours among people who inject drugs.

AIM: We tested the efficacy of a brief intervention based on motivational interviewing (MI) to reduce high-risk injection behaviours over a 6-month period among people who inject drugs (PWID). DESIGN: A single-site two-group parallel randomized controlled trial comparing MI with a brief educational intervention (EI). SETTING: A study office located in downtown Montréal, Canada, close to the community-based harm reduction programmes where PWID were recruited. PARTICIPANTS: PWID who had shared drug injection equipment or shared drugs by backloading or frontloading in the month prior to recruitment were randomized to either the MI (112) or EI (109) groups. INTERVENTION: The MI aimed to (1) encourage PWID to voice their desires, needs and reasons to change behaviours; (2) boost motivation to change behaviours; and (3) when the person was ready, support the plan he or she chose to reduce injection risk behaviours. The EI consisted of an individual session about safe injection behaviours. MEASUREMENTS: The primary outcome was defined as having any of these risk behaviours at 6 months: having shared syringes, containers, filters or water to inject drugs in the previous month and backloading/frontloading; each behaviour was examined separately, as secondary outcomes. FINDINGS: The probability of reporting a risk injection behaviour decreased in both the MI and the EI groups. At 6-month follow-up, participants who reported any risk behaviours were 50% [odds ratio (OR) = 0.50; confidence interval (CI) = 0.13-0.87] less likely to be in the MI group than in the EI group as well as those who reported sharing containers (OR = 0.50; CI = 0.09-0.90). PWID who reported sharing equipment excluding syringes were 53% less likely to be in the MI group (OR = 0.47; CI = 0.11-0.84). CONCLUSIONS: A brief motivational interviewing intervention was more effective than a brief educational intervention in reducing some high risk injecting behaviours up in the subsequent 6 months.

Drug use patterns in the presence of crack in downtown Montréal.

INTRODUCTION AND AIMS: A study was undertaken to verify reports of an increasing presence of crack in downtown Montréal, and to investigate the influence of crack availability on current drug use patterns among street-based cocaine users. DESIGN AND METHODS: The study combined both qualitative and quantitative methods. These included long-term intensive participant observation carried out by an ethnographer familiar with the field and a survey. The ethnographic component involved observations and unstructured interviews with 64 street-based cocaine users. Sampling was based on a combination of snowballing and purposeful recruitment methods. For the survey, structured interviews were conducted with a convenience sample of 387 cocaine users attending HIV/HCV prevention programs, downtown Montréal. RESULTS: A gradual shift has occurred in the last 10 years, with the crack street market overtaking the powder cocaine street market. Although the data pointed to an increase in crack smoking, 54.5% of survey participants both smoked and injected cocaine. Drug market forces were major contributing factors to the observed modes of cocaine consumption. While the study focused primarily on cocaine users, it became apparent from the ethnographic fieldwork that prescription opioids (POs) were very present on the streets. According to the survey, 52.7% of participants consumed opioids, essentially POs, with 88% of them injecting these drugs. DISCUSSION AND CONCLUSIONS: Despite the increased availability of crack, injection is still present among cocaine users due at least in part to the concurrent increasing popularity of POs.

High resting triacylglycerol turnover of rainbow trout exceeds the energy requirements of endurance swimming.

Fish may use lipoproteins instead of albumin-bound fatty acids to fuel endurance exercise, but lipoprotein kinetics have never been measured in ectotherms. In vivo bolus injections of labeled very-low-density lipoproteins ((3)H-VLDL labeled in vivo from donor fish) and continuous infusions of Intralipid (3H-labeled artificial emulsion) were used to investigate the effects of prolonged exercise (6 h at 1.5 body length/s) and heparin (600 U/kg) on the turnover rate of circulating triacylglycerol (TAG) in rainbow trout. We hypothesized that swimming would stimulate TAG turnover rate to fuel working muscles and that heparin would reduce flux by releasing lipoprotein lipase (LPL) from endothelial cells. Results from both tracer methods show that the baseline TAG turnover rate of trout ranges from 24 to 49 mumol TAG.kg(-1) x min(-1) and exceeds all values measured to date in endotherms. More important, this high resting turnover rate is not stimulated during swimming, because it can already cover several times the energy requirements of locomotion. The fact that heparin causes a 50% decrease in baseline TAG turnover rate suggests that fish LPL must be bound to the endothelium for normal tissue uptake of fatty acids supplied by lipoproteins, as in mammals. We propose that the high resting TAG turnover rate of rainbow trout could be needed by ectotherms for rapid restructuring of membrane phospholipids. The continuous tracer infusion method implemented here could be a versatile tool to investigate the potential role of lipoproteins in providing fatty acids for rapid homeoviscous adaptation.

In vivo regulation of rainbow trout lipolysis by catecholamines.

Lipolysis provides fatty acids that support key life processes by functioning as membrane components, oxidative fuels and metabolic signals. It is commonly measured as the rate of appearance of glycerol (Ra glycerol). Its in vivo regulation by catecholamines has been thoroughly investigated in mammals, but little information is available for ectotherms. Therefore, the goals of this study were, first, to characterize the effects of the catecholamines norepinephrine (NE) and epinephrine (Epi) on the lipolytic rate of intact rainbow trout (Oncorhynchus mykiss) and, second, to determine whether the plasma glycerol concentration is a reliable index of Ra glycerol. Our results show that baseline Ra glycerol (4.6+/-0.4 micromol kg(-1) min(-1)) is inhibited by NE (-56%), instead of being stimulated, as in mammals, whereas Epi has the same activating effect in both groups of vertebrates (+167%). NE-induced inhibition of fish lipolysis might play a particularly important role during aquatic hypoxia, when survival often depends on regulated metabolic depression. The plasma glycerol concentration is a poor predictor of Ra glycerol, and it should not be used as an index of lipolysis. Trout maintain a particularly high baseline lipolytic rate because only 13% of the fatty acids provided are sufficient to support total energy expenditure, whereas the remaining fatty acids must undergo reesterification (87%).

Lipid mobilization of long-distance migrant birds in vivo: the high lipolytic rate of ruff sandpipers is not stimulated during shivering.

For long migrations, birds must rely on high flux capacities at all steps of lipid metabolism, from the mobilization of adipose reserves to fatty acid oxidation in flight muscle mitochondria. Substrate kinetics and indirect calorimetry were used to investigate key parameters of lipid metabolism in a highly aerobic shorebird: the ruff sandpiper Philomachus pugnax. In this study, we have quantified the effects of cold exposure because such measurements are presently impossible during flight. Lipolytic rate was monitored by continuous infusion of 2-[(3)H]-glycerol and lipid oxidation by respirometry. Plasma lipid concentrations (non-esterified fatty acids, neutral lipids and phospholipids) and their fatty acid composition were also measured to assess whether cold exposure causes selective metabolism of specific lipids. Results show that shivering leads to a 47% increase in metabolic rate (44.4+/-3.8 ml O(2)kg(-1) min(-1) to 65.2+/-8.1 ml O(2) kg(-1) min(-1)), almost solely by stimulating lipid oxidation (33.3+/- 3.3 ml O(2) kg(-1) min(-1) to 48.2+/-6.8 ml O(2) kg(-1) min(-1)) because carbohydrate oxidation remains close to 11.5+/- 0.5 ml O(2) kg(-1) min(-1). Sandpipers support an unusually high lipolytic rate of 55-60 micromol glycerol kg(-1) min(-1). Its stimulation above thermoneutral rates is unnecessary during shivering when the birds are still able to re-esterify 50% of released fatty acids. No changes in plasma lipid composition were observed, suggesting that cold exposure does not lead to selective metabolism of particular fatty acids. This study provides the first measurements of lipolytic rate in migrant birds and shows that their capacity for lipid mobilization reaches the highest values measured to date in vertebrates. Extending the limits of conventional lipid metabolism has clearly been necessary to achieve long-distance migrations.

Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.

Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.

Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

Energetics of a long-distance migrant shorebird (Philomachus pugnax) during cold exposure and running.

The metabolic consequences of cold exposure and exercise are not well characterized in birds. Ruff sandpipers Philomachus pugnax are migrant shorebirds traveling between Africa and Siberia for up to 30,000 km annually. Our goal was to quantify the fuel selection pattern of these remarkable athletes during shivering and terrestrial locomotion. We used indirect calorimetry and nitrogen excretion analysis to measure their rates of lipid, carbohydrate and protein oxidation at different temperatures (22, 15, 10 or 5 degrees C) and different treadmill speeds (15, 20, 25, 30, 35 or 40 m min(-1)). Results show that lipid oxidation supplies nearly all the energy necessary to support shivering and running, and that the pattern of oxidative fuel selection is independent of shivering or running intensity. During shivering, total ATP production is unequally shared between lipids (82%), carbohydrates (12%) and proteins (6%). During running, lipids remain the dominant substrate (66%), with carbohydrates (29%) and proteins (5%) playing more minor roles. The prevailing use of lipids during intense shivering and high-speed running is not consistent with the fuel selection pattern observed in exercising and cold-exposed mammals. The exact mechanisms allowing birds to use lipids at extremely high rates are still largely unexplored, and quantifying the relative importance of different fuels during long-distance flight remains a major challenge for future research.