Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes¹. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear^2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor ?-like (GFRAL)-dependent suppression of food intake^4,5,6,7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL–?-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

The study objective is to evaluate the influence of attrition from a paediatric weight management program (PWM) on health indicators over a 2-year period. Among 269 children enrolled, 19% had no clinic treatment visit, 16% had treatment visits only up to 6?months, 23% up to 1?year and 42% had at least one clinic visit after 1?year (No Attrition). Greater declines in BMI z-score and body fat were seen at 2?years in children with No Attrition, while improvements in HRQoL were similar for all attrition groups. Children who attended at least one treatment visit reported improved HRQoL up to 2?years, regardless of duration in clinic. In contrast, declines in body fat and BMI z-score were greater at 2?years for those with at least one visit after 1?year. Continued efforts to reduce attrition are likely to improve anthropometric health outcomes during PWM.

Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking.

Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor ? coactivator-1? activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.

Rates of human obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) have risen faster than anticipated and cannot solely be explained by excessive caloric intake or physical inactivity. Importantly, this effect is also observed in many other domesticated and non-domesticated mammals, which has led to the hypothesis that synthetic environmental pollutants may be contributing to disease development. While the impact of these chemicals on appetite and adipogenesis has been extensively studied, their potential role in reducing energy expenditure is less studied. An important component of whole-body energy expenditure is adaptive and diet-induced thermogenesis in human brown adipose tissue (BAT). This review summarizes recent evidence that environmental pollutants such as the pesticide chlorpyrifos inhibit BAT function, diet-induced thermogenesis and the potential signaling pathways mediating these effects.

Diet influences intestinal microbiota, inflammation, and metabolism. Kawano et al. show that dietary sugar engaged upper gut innate lymphoid cells to replace segmented filamentous bacteria with a pathobiont. Added sugar worsened early metabolic disease by lowering protective Th17 immunity, thereby promoting intestinal lipid absorption and obesity in high-fat-diet-fed mice.

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins to regulate critical processes in health and disease. A mechanistic understanding of the role(s) of CARM1 in skeletal muscle biology is only gradually emerging. The purpose of this study was to elucidate the function of CARM1 in regulating the maintenance and plasticity of skeletal muscle. We used transcriptomic, methylproteomic, molecular, functional, and integrative physiological approaches to determine the specific impact of CARM1 in muscle homeostasis.This study uncovers the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology.

The primary objective of this pilot randomized controlled trial (RCT) is to assess the feasibility of an intervention that screens for and addresses the social needs of children and families enrolled in a pediatric weight management clinic. We will conduct a single-center, pilot RCT of 40 families with children enrolled in a pediatric weight management program at a tertiary children’s hospital in Ontario, Canada. Families who are experiencing unmet social needs will be randomized to either a community navigator or self-navigation of community resources. This study is important because it will aim to improve the treatment of pediatric obesity by testing the feasibility of an intervention that addresses unmet social needs.

Understanding the impact of maternal health behaviours and social conditions on childhood nutrition is important to inform strategies to promote health during childhood. Data were collected from the Indigenous Birth Cohort (ABC) study, a prospective birth cohort formed in partnership with an Indigenous community-based Birthing Centre in southwestern Ontario, Canada. This study highlights the positive impact of health care provision by Indigenous midwives and confirms that higher maternal social advantage has a positive impact on child nutrition.

Obesity is a global public health concern. Given the widespread disruption caused by the SARS-CoV-2 pandemic, it is important to evaluate its impact on children with chronic health conditions. This study examines the health of paediatric patients with obesity enrolled in a tertiary hospital weight management program, before and 1 year into the COVID-19 pandemic. This is a retrospective chart review of patients aged 2 to 17 years enrolled in a paediatric weight management clinic. Mental health outcomes (i.e., new referrals to psychologist, social work, eating disorder program, incidence of dysregulated eating, suicidal ideation, and/or self-harm) and physical health (anthropometric measures) were compared before and 1 year into the pandemic. The pandemic has impacted the mental and physical health of children with obesity engaged in a weight management clinic. While our study provides evidence of a negative impact on mental health outcomes and less improvement in anthropometric measures, future research when patients return to in-person care will enable further examination of our findings with additional objective measures.

A recent randomized controlled trial demonstrated that a community-based, telephone-delivered diabetes health coaching intervention was effective for improving diabetes management. Our aim in this study was to determine whether this intervention is also cost-effective. An economic evaluation, in the form of a cost-utility analysis (CUA), was used to assess the cost-effectiveness of the coaching intervention from a public payer’s perspective. All direct medical costs, as well as intervention implementation, were included. The outcome measure for the CUA was quality-adjusted life-year (QALY). Uncertainty of cost-effectiveness results was estimated using nonparametric bootstraps of patient-level costs and QALYs in the coaching and control arms. A cost-effectiveness acceptability curve was used to express this uncertainty as the probability that diabetes health coaching is cost-effective across a range of values of willingness-to-pay thresholds for a QALY. A community-based, telephone-delivered diabetes health coaching intervention is cost-effective.

Exercise?based cardiac rehabilitation leads to improvements in cardiovascular function in individuals with coronary artery disease. The cardiac effects of coronary artery disease (CAD) can be quantified using clinical echocardiographic measures, such as ejection fraction (EF). Measures of cardiovascular function typically only used in research settings can provide additional information and maybe more sensitive indices to assess changes after exercise?based cardiac rehabilitation. These additional measures include endothelial function (measured by flow?mediated dilation), left ventricular twist, myocardial performance index, and global longitudinal strain. To investigate the cardiovascular response to 12 week of either traditional moderate?intensity (TRAD) or stair climbing?based high?intensity interval (STAIR) exercise?based cardiac rehabilitation using both clinical and additional measures of cardiovascular function in individuals with CAD. Measurements were made at baseline (BL) and after supervised (4wk) and unsupervised (12 week) of training. There were no changes in any other clinical or additional measures of cardiovascular function. The small increase in cardiac apical rotation observed after 4 weeks of training may indicate an early change in cardiac function. A larger overall training stimulus may be needed to elicit other cardiovascular function changes.

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.

Type 2 diabetes and obesity increase the risk of developing colorectal cancer (CRC). The first-line type 2 diabetes medication metformin may reduce colorectal cancer, but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known. We find that compared to chow-fed controls, syngeneic CRC tumor growth is increased when mice are fed HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor. These data suggest a potential novel mechanism for the chemo-preventative effects of metformin in people with type 2 diabetes.

Polycyclic aromatic compounds (PACs) are a broad class of contaminants ubiquitously present in the environment due to natural and anthropogenic activities. Previous studies have shown that PACs possess endocrine disruptive properties as these compounds often interfere with hormone signaling and function. Investigation into the impact of substituted PACs including halogenated, heterocyclic, and alkylated PACs on mammalian reproduction has been largely overlooked despite the fact that these compounds are found in higher abundance in free-ranging wildlife. This review aims to discuss current literature on the effects of PACs on the ovary in mammals, with a particular focus on folliculogenesis, steroidogenesis and angiogenesis, which are key processes necessary for proper ovarian functions.

Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD. This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD. Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention.

Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.

Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

Paediatric weight management interventions delivered to the parents of young children with obesity result in small declines in BMI z score. The results should be interpreted cautiously as they were inconsistent and the quality of the evidence was low.

Childhood obesity is a growing worldwide problem. In adults, lower cold-induced brown adipose tissue (BAT) activity is linked to obesity and metabolic dysfunction; this relationship remains uncertain in children. In this cross-sectional study, we compared cold-induced supraclavicular (SCV) BAT activity (percent change in proton density fat fraction (PDFF) within the SCV region after one hour of whole-body cold exposure (18°C), using magnetic resonance imaging (MRI)) in 26 boys aged 8-10 years; 13 with normal body mass index (BMI), and 13 with overweight/obesity. Anthropometry, body composition, hepatic, and visceral fat (VAT), and pre- and post-cold PDFF of the subcutaneous adipose tissue (SAT) in the posterior neck region and the abdomen were measured. Thus, in young boys, as in adults, BAT activity is lower in those with overweight/obesity, suggesting that restoring activity may be important for improving metabolic health.

Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardio-respiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown. Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12-weeks of cycling can recuperate clinical, and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients. With no available cures, our data supports the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1.

Exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites in the Alberta Oil Sands Region can impair reproductive health. We have shown that NAFC exposure results in a significant upregulation of GDF15 in placental trophoblasts. However, little is known regarding the mechanism(s) underlying NAFC-induced increases in GDF15 production during early placentation. The goal of this study was to examine the effects of NAFC exposure on the regulation of critical transcription factors of GDF15 in extravillous trophoblast cells. Of these transcription factors, inflammatory mediators including prostaglandins have been reported to inhibit proliferation and migration of trophoblast cells in vitro. Hence, the secondary goal of this study was to determine whether inflammation mediated through prostaglandin production is critical to GDF15 secretion. These findings suggest that while NAFC may affect GDF15 production, it is not exclusively a result of prostaglandin-mediated inflammation. This study provides new insights into the mechanisms by which NAFC may adversely affect placental trophoblast cell function in mammals.

This study explores growth and body composition trajectories in infants meeting the WHO Multicentre Growth Reference Study (MGRS) eligibility criteria. We evaluated which anthropometric measure (body mass index (BMI), weight for length or mid upper arm circumference) was most closely related to adiposity. Of the 225 infants with body composition measures, 187 met the WHO MGRS criteria. Their length and weight curves were comparable with WHO growth curves. Trajectory curves for fat and fat-free mass were developed. Of the anthropometric measures, BMI z score was most closely related to fat mass index z score at all timepoints. This study presents body composition trajectories for infants meeting the WHO growth standard criteria. BMI z score is the best anthropometric metric to estimate adiposity in infants.

Since the first national guideline for managing obesity in adults and children in Canada was published in 2007, new evidence has emerged and guideline standards have evolved. Our purpose is to describe the protocol used to update the Canadian clinical practice guideline for managing pediatric obesity.

In this meta-analysis, approximately 1 in 5 girls with T2D had PCOS, but the results of this meta-analysis should be considered with caution because studies including the larger numbers of girls did not report the criteria used to diagnose PCOS, which is a challenge during adolescence. The associations of obesity and race with PCOS prevalence among girls with T2D need further evaluation to help define at-risk subgroups and implement early assessment and treatment strategies to improve management of this T2D-related comorbidity.

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.

The global prevalence of hypertension in children and adolescents has increased over the past 2 decades and is the strongest predictor of adult hypertension. South Asians have an increased prevalence of metabolic syndrome associated risk factors including abdominal obesity, diabetes, and hypertension. All these factors contribute to their increased cardiovascular disease burden. Accurate and early identification of hypertension in South Asian children is a necessary aspect of cardiovascular disease prevention. Ambulatory blood pressure monitoring (ABPM) is considered the gold-standard for pediatric blood pressure (BP) measurement. However, its utilization is limited due to the lack of validated normative reference data in diverse, multiethnic pediatric populations.

Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved mechanisms to generate fatty acids from alternative carbon sources, through a process known as de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with a wide variety of pathologies. Inhibiting core enzymes of DNL, including citrate/isocitrate carrier (CIC), ATP- citrate lyase (ACLY), acetyl- CoA carboxylase (ACC) and fatty acid synthase (FAS), represents an attractive therapeutic strategy. Despite challenges related to efficacy, selectivity and safety, several new classes of synthetic DNL inhibitors have entered clinical- stage development and may become the foundation for a new class of therapeutics.

Metabolic enhancement (ME) supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.

Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn’s disease (CD). Factors that lead to the development of impaired autophagy during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin [5-hydroxytryptamine;(5-HT)] and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.

Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care.