Emily J. Dhurandhar

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7). Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

The effectiveness of breakfast recommendations on weight loss: a randomized controlled trial

BACKGROUND Breakfast is associated with lower body weight in observational studies. Public health authorities commonly recommend breakfast consumption to reduce obesity, but the effectiveness of adopting these recommendations for reducing body weight is unknown. OBJECTIVE We tested the relative effectiveness of a recommendation to eat or skip breakfast on weight loss in adults trying to lose weight in a free-living setting. DESIGN We conducted a multisite, 16-wk, 3-parallel-arm randomized controlled trial in otherwise healthy overweight and obese adults [body mass index (in kg/m²) between 25 and 40] aged 20-65 y. Our primary outcome was weight change. We compared weight change in a control group with weight loss in experimental groups told to eat breakfast or to skip breakfast [no breakfast (NB)]. Randomization was stratified by prerandomization breakfast eating habits. A total of 309 participants were randomly assigned. RESULTS A total of 283 of the 309 participants who were randomly assigned completed the intervention. Treatment assignment did not have a significant effect on weight loss, and there was no interaction between initial breakfast eating status and treatment. Among skippers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.71 ± 1.16, -0.76 ± 1.26, and -0.61 ± 1.18 kg for the control, breakfast, and NB groups, respectively. Among breakfast consumers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.53 ± 1.16, -0.59 ± 1.06, and -0.71 ± 1.17 kg for the control, breakfast, and NB groups, respectively. Self-reported compliance with the recommendation was 93.6% for the breakfast group and 92.4% for the NB group. CONCLUSIONS A recommendation to eat or skip breakfast for weight loss was effective at changing self-reported breakfast eating habits, but contrary to widely espoused views this had no discernable effect on weight loss in free-living adults who were attempting to lose weight.

Template to improve glycemic control without reducing adiposity or dietary fat

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

Predicting adult weight change in the real world: a systematic review and meta-analysis accounting for compensatory changes in energy intake or expenditure

Background:Public health and clinical interventions for obesity in free-living adults may be diminished by individual compensation for the intervention. Approaches to predict weight outcomes do not account for all mechanisms of compensation, so they are not well suited to predict outcomes in free-living adults. Our objective was to quantify the range of compensation in energy intake or expenditure observed in human randomized controlled trials (RCTs).Methods:We searched multiple databases (PubMed, CINAHL, SCOPUS, Cochrane, ProQuest, PsycInfo) up to 1 August 2012 for RCTs evaluating the effect of dietary and/or physical activity interventions on body weight/composition. Inclusion criteria: subjects per treatment arm ⩾5; ⩾1 week intervention; a reported outcome of body weight/body composition; the intervention was either a prescribed amount of over- or underfeeding and/or supervised or monitored physical activity was prescribed; ⩾80% compliance; and an objective method was used to verify compliance with the intervention (for example, observation and electronic monitoring). Data were independently extracted and analyzed by multiple reviewers with consensus reached by discussion. We compared observed weight change with predicted weight change using two models that predict weight change accounting only for metabolic compensation.Findings:Twenty-eight studies met inclusion criteria. Overfeeding studies indicate 96% less weight gain than expected if no compensation occurred. Dietary restriction and exercise studies may result in up to 12–44% and 55–64% less weight loss than expected, respectively, under an assumption of no behavioral compensation.Interpretation:Compensation is substantial even in high-compliance conditions, resulting in far less weight change than would be expected. The simple algorithm we report allows for more realistic predictions of intervention effects in free-living populations by accounting for the significant compensation that occurs.

PPARγ-Independent Increase in Glucose Uptake and Adiponectin Abundance in Fat Cells

Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/3T3 that have impaired PPARγ expression, and 5) PPARγ-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARγ served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARγ, Ad36 significantly enhanced glucose uptake and PPARγ, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARγ. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARγ induction associated with TZD actions.

E4orf1: a novel ligand that improves glucose disposal in cell culture.

Reducing dietary fat intake and excess adiposity, the cornerstones of behavioral treatment of insulin resistance(IR), are marginally successful over the long term. Ad36, a human adenovirus, offers a template to improve IR, independent of dietary fat intake or adiposity. Ad36 increases cellular glucose uptake via a Ras-mediated activation of phosphatidyl inositol 3-kinase(PI3K), and improves hyperglycemia in mice, despite a high-fat diet and without reducing adiposity. Ex-vivo studies suggest that Ad36 improves hyperglycemia in mice by increasing glucose uptake by adipose tissue and skeletal muscle, and by reducing hepatic glucose output. It is impractical to use Ad36 for therapeutic action. Instead, we investigated if the E4orf1 protein of Ad36, mediates its anti-hyperglycemic action. Such a candidate protein may offer an attractive template for therapeutic development. Experiment-1 determined that Ad36 ‘requires’ E4orf1 protein to up-regulate cellular glucose uptake. Ad36 significantly increased glucose uptake in 3T3-L1 preadipocytes, which was abrogated by knocking down E4orf1 with siRNA. Experiment-2 identified E4orf1 as ‘sufficient’ to up-regulate glucose uptake. 3T3-L1 cells that inducibly express E4orf1, increased glucose uptake in an induction-dependent manner, compared to null vector control cells. E4orf1 up-regulated PI3K pathway and increased abundance of Ras–the obligatory molecule in Ad36-induced glucose uptake. Experiment-3: Signaling studies of cells transiently transfected with E4orf1 or a null vector, revealed that E4orf1 may activate Ras/PI3K pathway by binding to Drosophila discs-large(Dlg1) protein. E4orf1 activated total Ras and, particularly the H-Ras isoform. By mutating the PDZ domain binding motif(PBM) of E4orf1, Experiment-4 showed that E4orf1 requires its PBM to increase Ras activation or glucose uptake. Experiment-5: In-vitro, a transient transfection by E4orf1 significantly increased glucose uptake in preadipocytes, adipocytes, or myoblasts, and reduced glucose output by hepatocytes. Thus, the highly attractive anti-hyperglycemic effect of Ad36 is mirrored by E4orf1 protein, which may offer a novel ligand to develop anti-hyperglycemic drugs.

Hunger in the Absence of Caloric Restriction Improves Cognition and Attenuates Alzheimer's Disease Pathology in a Mouse Model

It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimers disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

Recent advances in understanding and mitigating adipogenic and metabolic effects of antipsychotic drugs

Although offering many benefits for several psychiatric disorders, antipsychotic drugs (APDs) as a class have a major liability in their tendency to promote adiposity, obesity, and metabolic dysregulation in an already metabolically vulnerable population. The past decade has witnessed substantial research aimed at investigating the mechanisms of these adverse effects and mitigating them. On July 11 and 12, 2011, with support from 2 NIH institutes, leading experts convened to discuss current research findings and to consider future research strategies. Five areas where significant advances are being made emerged from the conference: (1) methodological issues in the study of APD effects; (2) unique characteristics and needs of pediatric patients; (3) genetic components underlying susceptibility to APD-induced metabolic effects; (4) APD effects on weight gain and adiposity in relation to their acute effects on glucose regulation and diabetes risk; and (5) the utility of behavioral, dietary, and pharmacological interventions in mitigating APD-induced metabolic side effects. This paper summarizes the major conclusions and important supporting data from the meeting.

The aetiology of obesity beyond eating more and exercising less.

Although recent increases in availability of energy dense, processed foods and reductions in institutionally driven physical activity have created an environment that is permissible for obesity to occur, several other factors may contribute to the development of obesity in this context. We review evidence for eleven such factors: endocrine disruptors, intrauterine effects, epigenetics, maternal age, differential fecundity and assortative mating by body mass index, microorganisms, reduction in variability of ambient temperatures, smoking cessation, sleep debt, and pharmaceutical iatrogenesis. Evidence for the role of endocrine disruptors, microorganisms, ambient temperatures, sleep and reproductive factors is accumulating, but additional research is needed to confirm the causative role of these factors in human obesity. However, the role of certain pharmaceuticals and smoking cessation in development of human obesity is clear. Practice points for consideration and future research needed are highlighted for each factor.

E4orf1 improves lipid and glucose metabolism in hepatocytes: a template to improve steatosis & hyperglycemia.

Hepatic steatosis often accompanies obesity and insulin resistance. The cornerstones of steatosis treatment include reducing body weight and dietary fat intake, which are marginally successful over the long term. Ad36, a human adenovirus, may offer a template to overcome these limitations. In vitro and in vivo studies collectively indicate that via its E4orf1 protein, Ad36 improves hyperglycemia, and attenuates hepatic steatosis, despite a high fat diet and without weight loss. Considering that hepatic insulin sensitivity, or the synthesis, oxidation, or export of fatty acid by hepatocytes are the key determinant of hepatic lipid storage, we determined the role of E4orf1 protein in modulating these physiological pathways. For this study, HepG2 cells, or mouse primary hepatocytes were transfected with E4orf1 or the null vector. Glucose output by hepatocytes was determined under gluconeogenic conditions (cAMP and dexamethasone, or glucagon exposure). Also, de-novo lipogenesis, palmitate oxidation, and lipid export as determined by apoB secretion were measured 48 h post transfection. Results show that compared to null vector transfected cells, E4orf1 significantly reduced glucose output in basal and gluconeogenic conditions. E4orf1 reduced de-novo lipogenesis by about 35%, increased complete fatty acid oxidation 2-fold (p<0.0001), and apoB secretion 1.5 fold(p<0.003). Response of key signaling molecules to E4orf1 transfection was in agreement with these findings. Thus, E4orf1 offers a valuable template to exogenously modulate hepatic glucose and lipid metabolism. Elucidating the underlying molecular mechanism may help develop therapeutic approaches for treating diabetes or non-alcoholic fatty liver disease(NAFLD).