Insulin & Dopamine in Overweight Youth

Transcription

1 Insulin & Dopamine in Overweight Youth What is on the menu for today Significance of early onset of overweight and hyperinsulinemia Role of insulin in energy homeostasis & as satiety factor Teresa Quattrin, MD Professor of Pediatrics Chair, Department of Pediatrics, University at Buffalo Pediatrician-in-Chief, Chief, Division of Endocrinology-Diabetes Women and Children s Hospital of Buffalo Dopamine (DA) role in energy homeostasis link between insulin & dopaminergic systems Age at onset vs. age at referral (n=181) % 5 Age (Mean + SD) 4 At onset of obesity Initial Endocrine Visit >14 Age (years) Quattrin et al. Pediatrics. 115: , 25 Do overweight children become overweight adults? Overweight tracks from childhood to adulthood: 51% of children who are obese between 3-5 years of age will become obese adults Children 3-5 years of age who a have a BMI > 85 th percentile are four time more likely to become obese adults

2 Prevalence of obesity reported in parents of obese youth What about a child s genetic predisposition? Parent Report CDC In children with BMI > 95 th percentile at 3-5 years of age, the prevalence of obesity in adulthood is 83% if parents are obese 2 1 Parental obesity is a primary risk factor for early adiposity rebound Maternal Obesity Paternal Obesity Obesity General Population What is adiposity rebound? The earlier the BMI rebound occurs, the higher the risk to be obese as adult A two-prong approach Pediatricians should identify overweight children and reach out to obese parents regarding need for family changes Internists should talk with obese parents about implementing changes for adults and children in the family

3 This is the growth curve of a tall girl She gained 1 pounds in 6 months, but did not look overweight BMI is 17.7 which is at the 85 percentile What is on the menu for today Significance of early onset of overweight and hyperinsulinemia Role of insulin in energy homeostasis & as satiety factor Dopamine (DA) role in energy homeostasis link between insulin & dopaminergic systems Homeostasis from Greek: ὅμοιος, homoios, "similar"; and ἵστημι, histēmi, "standing still Is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition Multiple dynamic equilibria adjustment and regulation mechanisms make homeostasis possible Homeostatic & non-homeostatic feeding Homeostatic feeding (HF) is driven by energy demands Non-homeostatic feeding (NHF) is driven by pleasure or palatability associated with food preference Insulin as Satiety Factor A vast body of research has shown that insulin is a satiety factor Insulin infused in the CNS leads to a decrease in the animals food intake and body weight Central administration of insulin increases insulin sensitivity in peripheral tissues & is associated with a reduction in hepatic glucose production A number of studies have shown that insulin and leptin decrease food reward and motivation to feed

4 Insulin as satiety factor Although some reports have suggested that insulin can be secreted within the CNS, the majority of insulin is transferred to the CNS with receptor-mediated transport Insulin and insulin receptors are present in the CNS Insulin and leptin in the CSF are decreased in obese animals It is possible that in humans with insulin resistance, despite high circulating insulin levels, insulin may be low also in CSF and/or act less efficiently as satiety factor in the CNS Insulin Is transported into the arcuate nucleus Inhibit NPY & AgRP neurons Stimulate POMC & alpha MSH neurons Low insulin levels observed in fasting lead to increased NPY & AgRP Endocrine News, August/Sept 25 Insulin & obesity: Chicken or Egg? Influence of the intra-uterine milieu In the animal model, a pup born to an obese mother with high insulin levels has the same weight of a pup born to a lean mom without elevated insulin levels Influence of the intra-uterine milieu High insulin levels as early as 4 years of age When the two babies are raised in the same environment and fed the same diet, the pup born to the obese mom gains weight inappropriately compared to the pup born to the lean mom! % 3 2 Insulin >15 mu/ml Insulin < 15 mu/ml >14 Quattrin et al. Pediatrics. 115: , 25 Age (years)

5 Homeostasis Model Assessment of Insulin resistance (HOMA-IR) HOMA-IR Widely employed to assess insulin sensitivity HOMA= Fasting Insulin x BG/45 Even with modest weight loss insulin sensitivity improves Roemmich JN et al: Metabolic Syndrome & related disorders 2:16, 24 Insulin in obesity Youth with overweight & hyperinsulinemia? In obese dogs less insulin is available to the brain as an adiposity signal Diet content can also affect brain insulin transfer Insulin loses its ability to act as adiposity signal with increased meal fat content To obtain preliminary data regarding energy intake (EI) in obese Normoinsulinemic (NI, <15 mu/ml) vs. Hyperinsulinemic (HI, >15 mu/ml) year old youth Assessments Procedures (I) Meals composed by a pre-determined variety of food including high/low energy food and high/low fat containing food choices Food was served in boxes and labeled by numbers Participants were instructed to consume as much or as little as they wished Assessments Procedures (II) The exact weights of the food were established via electronic scale before and after the meal. The energy intake and meal composition was calculated based on food labels The meal was served in a quiet room. Study participant alerted us via walkie-talkie when she/he had completed the meal Participants were not aware that they were observed during the meal

6 Study test meal Subjects (mean + SD) Low High Calories Fat CHO Item Volume Item Volume (kcal/gram) (kcal) (kcal) Water 1 cup Pop 1 cup 9 skim milk 1 cup Chocolate Milk 1 cup (.37/g) Dannon Light & Fit 4 1 container 28 Dannon lacreme yogurt 1 container yogurt (.35/g) 8 Dole apple & caramel Fruit (Apple/Orange) container (.52/g) crème Calories (kcal/gram) 1 (.43/g) 21 (.83/g) 14 (1.2/g) 12 (.98/g) Fat CHO (kcal) (kcal) HI NI p-value Mean age (years) <.1 Males/females 4/5 3/1 Caucasian/AA/others 7/1/1 7/4/2 BMI (SDU) Fasting insulin (mu/ml) <.1 Kellogg s Special K cereal 1 cup 11 (3.5/g) 88 Post Banana Nut Crunch 1 cup 24 (4/g) Lay s Light chips 1 ½ cups 75 (2.7/g) 75 Lay s Classic chips 1 ½ cups 15 (5.4/g) 9 6 Energy Intake (EI) in NI vs HI Energy intake (EI) in NI vs. HI (Kcal/kg body weight) NI group HI group Total EI EI from Fat EI from CHO EI (Kcal) NI HI Total EI EI from Fat EI from CHO p Total EI/kg EI from CHO/kg EI from fat/kg HI NI p What is on the menu for today Significance of early onset of overweight and hyperinsulinemia Role of insulin in energy homeostasis & as satiety factor Dopamine (DA) role in energy homeostasis link between insulin & dopaminergic systems Nigrostriatal Pathway Mesolimbic Reward Pathway Ventral tegmental area (VTA) to Nucleus Accumbens, Amygdala, Hypothalamus and Prefrontal area Tuberoinfundibular pathway DA is the neurotransmitter in the Reward pathway which is believed to drive eating Neuroimaging studies indentified regions of the brain (especialy the orbitofrontal cortex) as responsible for linking food to edonic experienece Adapted from

7 Dopamine role in motivation & addiction DA systems are also necessary for incentives, i.e. motivate an animal to perform & seek a given behavior DA is released following drug use inducing reinforcement Dopamine as appetite regulator Plays an important role in the regulation of eating behaviors & reward Is a powerful inhibitor of NPY (potent stimulator of food intake) Animal models have shown that DA markedly reduces adiposity and insulin resistance Dopamine & obesity Stimulant medications that enhance dopamine response are associated with anorexia and weight loss Obesity is associated with abnormal DA activity related to abnormal DA receptors Reinholz hypothesized that overweight may be due to: Lower DA activity leading to excessive food intake or A behavioral mechanism of compensating for decreased DA signaling after DA overstimulation (after overconsumption of highly palatable food) Dopamine receptors (R) Five subtypes of DA Rs have been identified and categorized in D1 and D2 Rs Both D1 and D2 Rs play a significant role in controlling feeding behavior D2 R agonists decrease NPY & weight gain in hyperglycemic obese mice D2 receptors in morbidly obese individuals Using Positron Emission Tomography (PET) scan Wang et al showed a significant reduction of D2 Rs in morbidly obese subjects compared to controls The D2 R decrease is similar to reductions reported in drug-addicted subjects D2 R concentration correlated with BMI ONLY in obese subjects. Thus the D2 Rs: May not regulate weight per se but rather compulsion to eat in the pathological eater May enhance more severe obesity if genetic and environmental variables are present DA D2 R genotypes, food reinforcement, obesity and energy intake 18 4 year olds n=45 non-obese; n=29 obese Not currently on a diet No medications that affect appetite or eating No eating disorders Must like study foods Courtesy of Dr. Epstein - modified Epstein et al (27). Behavioral Neuroscience, 121,

8 Study Design Two visits separated by 1 week First visit = taste test Measure energy intake Take DNA sample Second visit = food reinforcement Participants complete reinforcement task Height/weight obtained Number of Button Presses Obese individuals find food more reinforcing than non-obese Non-obese (n=45) Obese (n=29) Variable ratio schedules of reinforcement Total Button Presses 2 * Non-Obese Obese Courtesy of Dr. Epstein Epstein et al (27). Behavioral Neuroscience, 121, Courtesy of Dr. Epstein Epstein et al (27). Behavioral Neuroscience, 121, Dopamine Transporter Protein (DAT) Variable Number Tandem Repeats (VNTR) polymorphism The DAT gene SLC6A3 is expressed in all dopaminergic neurons The DAT protein product binds DA presynaptically DAT is responsible for the re-uptake of dopamine into the neurons and has a role in regulating dopamine release DAT is the primary mechanism through which DA is cleared from the synapses Chromosome 5 DAT Gene 5 3 Untranslated Region Region (GAC CTC) n VNTR VNTR polymorphism is found in the 3 untranslated region of the DAT gene Each of these VNTR consists of a 4 base pair sequence and most frequently occurs as nine or ten tandem repeat units DAT Allele frequency Daniel et al. 28 Kang et al Rowe et al Doucette- Stamm et al /1 9/1 9/9 58% 32% 5% 48% 42% 1% 46% 44% 1% 52% 38% 7% Methylphenidate Methylphenidate (MPH) is a selective DAT inhibitor that increases brain DA level and activity shortly after oral administration Appetite decrease was observed in 26% of patients treated with MPH Therapeutic response to MPH can be highly variable depending on dopamine genotypes Leddy et al demonstrated that in obese adults a single dose of MPH resulted in 3% decrease in energy intake

9 Hypothesis Increased brain dopamine levels via single dose of MPH will result in decrease energy intake compared to placebo in obese youth aged 1-18 years Research Design Randomized single-blind placebo controlled within subject study Subjects received study drug (.3 mg/kg) or placebo followed by a 1-hour interval that allowed the study drug to take effect. Subjects were offered a tray with variety of high & low energy choices Energy intake: MPH vs Placebo Insulin influences DA activity Total EI EI from Fat EI from CHO placebo MPH Energy intake (EI) (Kcal) Placebo MPH p value Total E I EI from Fat EI from CHO In vivo and in vitro insulin affects expression and activity of DAT, increasing DAT mrna levels ultimately leading to increasing DA clearance Normally functioning insulin would decrease the rewarding aspect of food mediated by DA Figlewicz hypothesis: bimodal effect of insulin on food reward Low insulin levels activate the DA system Intermediate/physiologic levels suppress DA system & decrease effect of food as reward Elevated levels as observed in states of insulin resistance (IR) lead to impaired DA function DAT distribution in HI and NI obese youth All subjects n=22 1/1 (n/%) 8 / 38% 5 4 9/1 1 / 47.7% 5 5 9/9 1 / 4.8% /1 2 / 9.5% 2 HI NI

10 Take away message Strides forward have been and are being made in learning about the mechanisms controlling feeding and contributing to obesity Complex interplay of genetic, neurobiologic and environmental factors have to be considered when planning prevention and treatment of obesity The role played by the DA system in regulating food intake/reward & its interaction with insulin is one of the factors that may affect the outcome of children who are environmentally and genetically predisposed to becoming obese adults