Andrea M. Haqq

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss

The enhanced decrease in circulating branched-chain amino acids and their metabolites after gastric bypass occurs by mechanisms other than weight loss. Dissecting the Quick Fix In the Wizard of Oz, when Dorothy encounters a split in the yellow brick road, the Scarecrow assures her that all paths lead to the land of Oz. We’ve witnessed the perils Dorothy met along the path she chose; however, we don’t know what she would have encountered had she followed another route to Oz. Similarly, obese patients with type 2 diabetes can take one of two paths to weight loss—dietary intervention or gastric bypass surgery (GBP). Although the end result—weight loss—is the same, the metabolic shifts that occur en route appear to differ. Now, Laferrère et al. show that in patients with equivalent weight loss, those who underwent GBP displayed a larger decrease in certain circulating amino acids than did subjects who pursued the dietary intervention path. This difference may help to explain why patients who opted for the surgical intervention boasted better improvement in glucose homeostasis—including enhanced insulin sensitivity—than did those who lost weight by controlling their dietary intake. Obese patients with type 2 diabetes strive to lose weight for reasons more momentous than an approaching swimsuit season. Weight loss can improve the body’s ability to metabolize glucose and thus stems the serious complications of diabetes. Patients often can reduce or forgo their diabetes medications. However, in such patients, glycemic control is improved to a greater extent within days after GBP—before weight loss occurs—than after diet-induced shedding of pounds and inches. Precisely why remains a mystery, but research in animal models has revealed that higher-than-normal blood concentrations of branched-chain amino acids (BCAAs) and their metabolites play a role in the loss of insulin sensitivity. Furthermore, recent studies in human patients show a robust positive correlation between insulin resistance and blood levels of BCAAs and their by-products. Finally, obese people have higher circulating concentrations of these amino acids compared to their lean counterparts; the same goes for individuals with versus without diabetes. These observations imply that the rapid reversal of diabetes symptoms in GBP patients may have something to do with BCAA metabolism. Here, the authors measured circulating amounts of a variety of amino acids and acylcarnitines—some of which are produced primarily from BCAA metabolism—to characterize the differential metabolic responses to weight loss induced by GBP versus dietary intervention in obese type 2 diabetes patients. Circulating concentrations of total amino acids, BCAAs, and BCAA metabolites all decreased significantly after GBP but not after dietary intervention, despite equivalent weight loss. These findings were consistent in two patient cohorts, one from the New York Obesity Nutrition Research Center and one from Duke University; in the latter group, the effects were shown to persist for months. These data support the notion that the surgical intervention promoted enhanced BCAA metabolism by mechanisms separate from weight loss and suggest that changes in circulating amino acids pave the road to the correction of glycemic control observed after GBP. Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

The association between insulin resistance and cytokines in adolescents: the role of weight status and exercise

Increased adiposity is associated with insulin resistance (IR) and an inflammatory response in adults. We tested the hypotheses that cytokines associated with adiposity are also correlated with IR in early adolescents and that these relationships are moderated by weight status, levels of vigorous physical activity (VPA), or maximal aerobic power (pVO2max). Body mass, stature, and a fasting blood sample were obtained from 120 midpubertal adolescents (60 girls and 60 boys). Habitual VPA was obtained by a survey. Predicted VO2max was determined using a cycle ergometer test. Weight status was based on body mass index (BMI) percentiles (normal weight=BMI<75th percentile, overweight=BMI>95th percentile). Glucose, insulin, adiponectin, resistin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 were measured; and IR index was based on the Homeostatic Model Assessment. Adiponectin, resistin, and TNF-alpha were associated with IR in all adolescents (R2=0.329, P<.001; R2=0.152, P=.001; and R2=0.141, P=.002; respectively); but interleukin-6 was not (R2=0.148, P=.114). The degree of association between adiponectin and IR was stronger in overweight than in normal-weight adolescents (P<.050). When regression models included weight status, neither TNF-alpha nor resistin was significantly related to IR (P>.050). Exercise did not moderate the association between these cytokines and IR. However, higher levels of VPA and/or pVO2max were associated with higher adiponectin, lower resistin, and lower TNF-alpha in at least one of the sexes. Our results indicate that the pathophysiology of obesity is already established in early adolescents. Increased adiposity, resulting in reduced adiponectin and increased resistin and TNF-alpha, may link these cytokines with IR in adolescents.

The Metabolic Phenotype of Prader-Willi Syndrome (PWS) in Childhood: Heightened Insulin Sensitivity Relative to Body Mass Index

CONTEXT Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC, but different from those of OCs. RESULTS Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P < 0.05) and similar to LC. Moreover, high-density lipoprotein levels were lower and triglycerides higher in OCs (P < 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P < 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P < 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1, macrophage chemoattractant protein-1, TNFα, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or alanine aminotransferase. CONCLUSIONS The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high-sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease.

Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: Changes during development

Background  Prader–Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear.

Hyperglycemic hyperosmolar syndrome in children: Pathophysiological considerations and suggested guidelines for treatment

A.H. received support from the Alberta Diabetes Institute and the Women & Children’s Health Research Institute at University of Alberta. These Clinical Practice Guideline are endorsed by the Lawson Wilkins Pediatric Endocrine Society. They were developed to be of assistance to endocrinologists by providing guidance and yperglycemic hyperosmolar syndrome (HHS), characterized by extreme elevations in serum glucose concentrations andhyperosmolalitywithout significant ketosis, has historically been infrequent in children. However, recent case reports and series describing HHS in children suggests that the incidence of this disorder may be increasing. The epidemiology of HHS in children and adolescents has been reviewed recently. HHS has a high mortality rate, and an understanding of the unique pathophysiology (Figure 1) of this condition is important to guide clinical decision-making. However, although treatment of diabetic ketoacidosis (DKA) in children is familiar to most clinicians, the management of HHS in youth presents a unique set of clinical challenges for which little guidance is currently available. The aim of this review is to discuss the pathophysiology of HHS and to provide broad treatment recommendations on the basis of the available literature and known physiological principles. Criteria for the diagnosis of HHS are listed in Table I. Although HHS is distinct from DKA (Table II; available at www.jpeds.com), patients may present with features of both conditions. HHS occurs less frequently in children than DKA, and some children with DKA can have severe hyperosmolality, complicating the recognition of HHS as a distinct entity. As a result, children with HHS are often treated with DKA protocols. However, the pathophysiology of HHS differs from DKA, and these differences should be considered in planning a rational therapeutic approach. Unlike the usual symptoms of DKA (hyperventilation, vomiting, and abdominal pain), which typically bring children to medical attention, the gradually increasing polyuria and polydipsia of HHS may go unrecognized. As a result, both dehydration and electrolyte loss are profound in HHS; in adults, fluid losses in HHS have been estimated to be twice those of DKA. Furthermore, obesity and hyperosmolality can make the clinical assessment of dehydration unreliable. It has been suggested on the basis of information from small case series that intake of copious quantities of carbonated sugar-enriched drinks before presentation may be a common feature of patients presenting with severe hyperglycemia. Because these case series lack control data, however, it is unclear whether this finding is specific to these patients.

Lower Brain-Derived Neurotrophic Factor in Patients with Prader-Willi Syndrome Compared to Obese and Lean Control Subjects

CONTEXT Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The potential role of BDNF in the etiology of the severe hyperphagia associated with PWS has not been previously explored. OBJECTIVE The aim was to compare BDNF concentrations in subjects with PWS and obese controls (OC) and lean controls (LC). DESIGN AND SETTING We conducted a cross-sectional study at an outpatient clinical research center. PARTICIPANTS We studied 13 subjects with PWS [five females and eight males; mean + or - sd: age, 11.0 + or - 4.1 yr; body mass index (BMI)-Z, 2.05 + or - 0.78], 13 OC (eight females, five males; age, 12.3 + or - 2.7 yr; BMI-Z, 2.18 + or - 0.61), and 13 LC (six females, seven males; age, 12.4 + or - 2.6 yr; BMI-Z, -0.57 + or - 0.73). MAIN OUTCOME MEASURE BDNF was measured in serum and plasma by ELISA. Analysis of covariance adjusted for age, sex, and BMI-Z. RESULTS All groups were comparable for age (P = 0.50) and sex distribution (P = 0.49). BMI-Z was comparable between PWS and OC (P = 0.89) and lower in LC (P < 0.001). Adjusted serum BDNF was comparable (P = 0.35) in OC (mean + or - sem: 13.5 + or - 1.2 ng/ml) and LC (19.2 + or - 1.3 ng/ml), but lower in PWS (8.3 + or - 1.2 ng/ml; P = 0.01 vs. OC; P = 0.03 vs. LC). Adjusted plasma BDNF in PWS (217 + or - 130 pg/ml) was lower than OC (422 + or - 126 pg/ml; P = 0.02), but statistically comparable with LC (540 + or - 143 pg/ml; P = 0.10). CONCLUSIONS Lower BDNF in PWS suggests insufficient central BDNF production because BDNF in peripheral circulation is believed to reflect cerebral BDNF output. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. Further studies are needed to confirm this preliminary pilot study in a larger cohort of patients with PWS.

Altered distribution of adiponectin isoforms in children with Prader–Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones

Objective  Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.

Autism spectrum disorder in Prader-Willi syndrome: A systematic review.

Prader–Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally‐derived genes on chromosome 15q11‐13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in some respects overlaps with autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by restricted or repetitive behaviors (RRBs) and social‐communication impairment. The goal of this review was to (i) review published literature investigating core ASD symptoms in PWS and (ii) provide a prevalence estimate of ASD in PWS. Two independent reviewers searched Medline, CINAHL, PsychINFO, Embase, and Web of Science to find studies that answered the research questions. Individuals with PWS demonstrate significant levels of RRBs and social‐communication impairment, in some reports reaching similar levels to those of non‐PWS ASD comparison groups. Individuals with UPD had more social‐communication impairment than those with DEL. Of 786 PWS participants, 210 (26.7%) were reported as meeting criteria for ASD, either based on clinical diagnosis or by exceeding clinical cut‐points on relevant ASD symptom measures. In studies that distinguished genetic subtypes, rates of ASD were higher in individuals with PWS with UPD (67 of 190; 35.3%) than those with DEL (47 of 254; 18.5%). Published data on the association of PWS and ASD to date are limited to sample means of 8 years of age and older. Further research is needed to identify early markers of ASD in PWS children, to support earlier diagnosis and intervention for this important comorbidity.