Sugar, Hormones, And Addiction

Educational Objectives

The goal of this program is to improve understanding of obesity and food addiction. After hearing and assimilating this program, the clinician will be better able to:

1. Discuss physiologic processes in the brain that are common to obesity and substance addiction.

2. Explain the role of leptin and insulin in the reward system.

3. Evaluate claims that food additives, such as salt, fat, and sugar, are addictive.

4. Question the validity of classifying substances as “generally recognized as safe.”

5. Distinguish the neurotransmitters involved in the sensation of pleasure from those associated with happiness.

Summary

Brain processes in obesity and addiction: physiologic processes in brain (primarily in structures of limbic system and orbitofrontal cortex [OFC]) similar in obesity and addiction; reward system — involves medial prefrontal cortex (PFC); lateral PFC involved in inhibition of reward; dopamine neurons from ventral tegmental area (VTA) transduce signal on nucleus accumbens; in normal brain, central gyrus and OFC tamp down signal and extinguish reward; in addicted brain, signal on nucleus accumbens overwhelms ability of hippocampus and lateral PFC to tamp down reward signal

Yale Food Addiction Scale: sample items — “I found myself continuing to consume certain foods even though I’m no longer hungry” (hedonic component); “I eat to the point where I feel physically ill” (bingeing component); “I find that when I start eating certain foods, I end up eating much more than planned”; study found that activation of anterior cingulate gyrus correlates with food addiction and changes in body mass index over time

Binge-eating disorder (BED): manifests as food addiction; patients with BED meet all criteria for substance dependence; bariatric surgery candidates with BED maintain addictive personality

Debate about concept of obesity and food addiction model: some scientists argue that individuals cannot be addicted to food because it is related to survival, and that not all individuals with obesity manifest food addiction (ie, concept does not apply as global theory for all individuals); other scientists argue that dismissal of food addiction is based on limited data; eating addiction — European group (NeuroFAST) stated that “eating addiction” rather than “food addiction” better captures addiction-like eating behaviors; eating addiction puts onus on individual rather than on food and food industry (ie, becomes personal responsibility and behavioral disorder, rather than public health issue)

Indirect effects on reward system: leptin — hormone produced by fat cells; after eating, signals to brain that sufficient energy available to engage in normal metabolic processes; when absence of leptin signal (because of deficiency of this hormone or inhibition of signal transduction), interpreted by brain as starvation; phenomena involved in obesity and starvation congruent (obesity can be considered “brain starvation”); insulin — 1) stimulates accumulation of fat cells; allows glucose or fatty acids to enter adipocytes for conversion to adipose tissue; 2) signals hypothalamus as part of satiety system (eg, “I’ve just eaten, and I don’t need to eat any more”)

Integration of pathways: nucleus accumbens produces dopamine and receives information from VTA; PFC tamps down effect of dopamine to prevent overeating and bingeing; leptin sends satiety signal to hypothalamus and instructs nucleus accumbens to tamp down dopamine; leptin receptors present in VTA

Leptin resistance: “sugar high” in nonobese leptin-sensitive children — when child eats cookie, insulin drives energy from cookie into adipocytes; leptin increases and signals sympathetic nervous system to burn off excess (by, eg, causing fidgeting); sympathetic tone increases, causing adipocytes to release some energy by activating hormone-sensitive lipase; obese leptin-resistant children — do not develop sugar high; do not receive signal that they have already eaten

Insulin resistance: with insulin sensitivity, dopamine clears more quickly when insulin increases, and insulin can blunt and extinguish phenomenon of reward; insulin-resistant mice found to gain weight excessively and have high leptin levels (which block leptin signals); study found that high degree of insulin resistance correlates with high energy intake; leptin and insulin pathways overlap and cross-talk; insulin is endogenous leptin antagonist

Chronic hyperinsulinemia: high insulin levels reduce leptin sensitivity, leading to increased hunger and greater sugar intake; promotes obesity by 1) driving energy into adipose tissue, 2) interfering with leptin signaling in hypothalamus (brain starvation), and 3) interfering with leptin signaling for dopamine clearance in nucleus accumbens (addiction)

“Limbic triangle” model: hypothalamus — area in which starvation registers; with leptin resistance, sympathetic nervous system shuts off (energy expenditure and physical activity low); vagus nerve sends message to pancreas to release extra insulin in order to store more energy (hyperinsulinemia drives obesity); nucleus accumbens — with insulin resistance, insulin does not signal nucleus accumbens; amygdala — cortisol stimulates appetite and causes significant insulin resistance, which further increases hyperinsulinemia and weight gain, and leads to metabolic syndrome

Direct effects on reward system: VTA sends projections to nucleus accumbens, amygdala, and PFC; food intake and reward — animal study found that infusing morphine into VTA increases food intake; downregulation of D2 receptors — D2 receptors downregulated in obesity in same fashion as in cocaine addiction; women who gain weight show reduction in striatal response to sweet taste (ie, desensitization) because of downregulation of dopamine receptors; 30% to 40% of obese individuals have Taq1A polymorphism of D2 receptor that causes reduced dopamine signaling for any given substrate exposure (higher quantity of substrate needed to signal reward, which correlates with increased weight gain)

NeuroFAST consensus opinion on food addiction: current evidence does not allow for conclusion that single food substance via single neurobiologic mechanism can account for fact that individuals overeat and develop obesity; in humans, no evidence that specific food, food ingredient, or food additive causes substance-based type of addiction (with exception of caffeine); alcoholic beverages not considered food; addictive overeating is clearly distinct from substance abuse disorders that cause addiction via specific mechanisms

Assessment of Components of “Fast Food”

Salt: rodents show increase in dopamine signaling in response to salt, leading to bingeing and cross-sensitization with amphetamines; humans have lower threshold (physiologically fixed); higher levels can be attributed to preference (can be retrained by, eg, following Dietary Approaches to Stop Hypertension diet); cravings for salty foods in children with salt-losing congenital adrenal hyperplasia can be reduced by giving fludrocortisone (Florinef [salt-retaining hormone]); salt is not addictive

Fat: rodents binge but show no signs of dependence; binge foods (eg, pizza, ice cream) high in fat but also high in carbohydrates and sugar; preference for fatty foods increases with addition of sugar; many individuals on Atkins-style diet with greater fat consumption have lower total caloric intake and lose weight; energy density more strongly associated with obesity than fat consumption; fat is not addictive

Caffeine: drug of dependence; caffeine is addictive but not toxic; dependence seen in children, adults, and adolescents; 30% of individuals who consume caffeine meet Diagnostic and Statistical Manual of Mental Disorders, (Fifth Edition; DSM-5) criteria for dependence; physiologic addiction established with development of headache, impaired task performance, fatigue, and withdrawal upon cessation of intake

Sugar: stimulates dopamine and opioid receptors; acts as natural analgesic; metabolism of alcohol and fructose nearly identical and results in de novo lipogenesis; functional magnetic resonance imaging (fMRI) studies — study in which individuals received milkshakes with differing fat and sugar composition found that fat stimulated somatosensory cortex, whereas only sugar stimulated nucleus accumbens; other data show no satiety or fullness (ie, no rise in insulin level) with consumption of fructose; glucose stimulated all parts of brain related to motor activity, whereas fructose stimulated entire limbic system; fructose is limbic system driver of reward

Criteria for addictiveness: animals — bingeing; withdrawal; craving; cross-sensitization with other drugs of abuse; rat studies show that sugar meets all these criteria; humans — based on DSM-5; includes tolerance and dependence

Dictionary definition of food: material essentially consisting of protein, carbohydrate, and fat, used in body of organism to sustain growth, repair, and vital processes, and to furnish energy; based on this definition, sugar is food

Nonfood energy sources: alcohol — not necessary for life; not required by any biochemical reaction in body; does not provide nutrition; toxic and causes death when consumed in excess; provides calories; food additive; trans fats — no longer listed as generally recognized as safe (GRAS) substance; cause metabolic syndrome, heart disease, and death

GRAS substances: defined as “generally recognized, among experts qualified by scientific training and experience to evaluate safety, as having been adequately shown through scientific procedures (or, in case of substance used in food prior to January 1, 1958 [eg, sugar], through either scientific procedures or experience based on common use in food) to be safe under conditions of its intended use”; based on toxicity rather than addiction; current level of sugar consumption never anticipated; current data demonstrate that sugar is toxic

Comparison of groceries purchased in 2012 vs 1982: purchase of meat decreased by 10% (attributed to recommendations to reduce fat intake); no changes seen in fruits and vegetables; purchase of grains and baked goods increased by 1%; dairy products decreased by 2.5%; 2-fold increase seen in purchases of processed foods and sweets

Summary: “it’s not about obesity”; “food additive addiction” more appropriate than “food addiction”; sugar is food additive; sugar is toxic and addictive in doses commonly consumed today, which were never intended; concept of GRAS should be revisited, and sugar should be removed from GRAS list

Pleasure vs happiness: pleasure — short-lived; visceral; associated with taking; usually experienced alone; extremes of pleasure lead to addiction; mediated by dopamine; happiness — long-lived; ethereal; associated with giving; usually experienced in social groupings; does not lead to addiction; mediated by serotonin; dopamine downregulates own receptor and serotonin; serotonin does not downregulate own receptor; “the more pleasure you seek, the more unhappy you get”; ways to increase serotonin and happiness — connect; contribute (to something bigger than yourself); cope (eg, sleep, exercise, meditation); cook

Forms of sugar: all sucrose or combinations of glucose and fructose; agave is 75% fructose; consumption of fructose causes crosslinking in intima of arteries and leads to atherosclerosis 7 times faster than glucose; honey, maple syrup, agave, high-fructose corn syrup, and sucrose “are all the same”

Audience question: countering food industry’s objection to legislating restrictions on sugar — food industry claims to have no culpability [in obesity crisis]; sugar can be classified as “hedonic substance”; in democratic society, markets allowed to determine demand until this mechanism fails; speaker states that markets ineffective for regulation of hedonic substances, and therefore, intervention by lawmakers necessary (as done in past for regulation of, eg, alcohol, tobacco)

Readings

Avena NM et al: Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39; Avena NM et al: Tossing the baby out with the bathwater after a brief rinse? The potential downside of dismissing food addiction based on limited data. Nat Rev Neurosci. 2012 Jun 20;13(7):514; Garber AK, Lustig RH: Is fast food addictive? Curr Drug Abuse Rev. 2011 Sep;4(3):146-62; Gearhardt AN et al: Preliminary validation of the Yale Food Addiction Scale. Appetite. 2009 Apr;52(2):430-6; Hebebrand J et al: “Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior. Neurosci Biobehav Rev. 2014 Nov;47:295-306; Lustig RH: Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nat Clin Pract Endocrinol Metab. 2006 Aug;2(8):447-58; Lustig RH: Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. 2010 Sep;110(9):1307-21; Mietus-Snyder ML, Lustig RH: Childhood obesity: adrift in the “limbic triangle”. Annu Rev Med. 2008;59:147-62; Stice E et al: Relative ability of fat and sugar tastes to activate reward, gustatory, and somatosensory regions. Am J Clin Nutr. 2013 Dec;98(6):1377-84; Stice E et al: Weight gain is associated with reduced striatal response to palatable food. J Neurosci. 2010 Sep 29;30(39):13105-9; Volkow ND et al: The addicted human brain: insights from imaging studies. J Clin Invest. 2003 May;111(10):1444-51; Ziauddeen H et al: Obesity and the brain: how convincing is the addiction model? Nat Rev Neurosci. 2012 Mar 14;13(4):279-86.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Lustig spoke in Napa, CA, at the 2017 Annual Meeting of the Northern California Psychiatric Society: Staging the Change in Psychiatry, presented March 24-26, 2017, by the Northern California Psychiatric Society. Please visit http://ncps.org/ for more information about this sponsor. The Audio Digest Foundation thanks Dr. Lustig and the Northern California Psychiatric Society for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PG070301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.