Obesity: A Really BIG Topic

Obesity: A Really BIG Topic Sharon Hausman Cohen, MD AAFP, AIHM and Katie Hansen, PhD University of Texas

Speaker Disclosure Dr. Hausman Cohen has disclosed that she is an employee of Intellexx DNA.

Obesity: A Really BIG Topic SCIENCE: Be able to describe how the leptin pathway is interrelated to the functions of genes in the hypothalamus, as well as how inflammation, fat absorption and insulin can contribute to obesity FOOD: See how specific food intake can be linked to obesity risk. EDUCATION: Acquire practical ways of discussing various obesity interventions and patterns with patients whether or not you have genomics.

Genetics Diet Sleep Mental and physical health and Level of physical activity Obesity is Complex

Genes Can Help Unravel Obesity But Anthropology Should Not Be Ignored Estimated that 40 70% of the variation in BMI can be explained by heritable factors. 140 gene variants that have been shown to increase susceptibility to obesity although many are linked Gene environment interactions are however what trigger majority of obesity. Diet modifies gene expression. Constant access to food and fat has happened quickly from evolutionary standpoint

Obesity gene variants can be grouped by how they increase risk: Gene expression in the hypothalamus Fatty acid metabolism, synthesis and storage Inflammation Insulin sensitivity

Hypothalamus: Appetite Regulation with Leptin and Ghrelin Leptin is made in adipose tissue and secreted after meals supposed to increase feelings of satiety Ghrelin is made in stomach and secreted when blood glucose levels are low; modulates insulin levels but also modulates hunger Leptin inhibits Ghrelin synthesis or it is supposed to

The Leptin Pathway as a Hunger Regulator Leptin is produced by white adipose tissue supposed to inhibit food intake White adipose tissue is longterm fuel reserve Storage form of fat that can be mobilized during starvation/ hunger How much white fat you have determines leptin levels Leptin is secreted into the bloodstream, then attaches to proteins, and is transported to the brain.

The Leptin Pathway as a Hormone Regulator in Normal Brain, Normal Weight Person In the brain leptin up regulates anorexigenic (MAKE YOU NOT HUNGRY) hypothalamic neuropeptides such as alpha MSH, which acts on the melanocortin 4 receptor (MC4R) (important in obesity) that suppress hunger

The Leptin Pathway as a Hormone Regulator in Normal Brain, Normal Weight Person Leptin binds to the leptin receptor and is supposed to down regulate some orexigenic (hunger producing) neuropeptides, such as the neuropeptide Y, agouti related peptide that make you hungry.

The Leptin Pathway as a Hormone Regulator in Normal Brain, Normal Weight Person Leptin also regulates fertility. If Leptin gets too low (starvation) it will prevent the LH surge and prevent ovulation.

Leptin in Obese However is up to 3x Higher Leptin Resistance seems to develop in Obesity But more on that later let s go back a few steps Al Maskari MY, Alnaqdy AA. Correlation between Serum Leptin Levels, Body Mass Index and Obesity in Omanis. Sultan Qaboos University Medical Journal. 2006;6(2):27 31.

A Deeper Look into How Genomics Increases Risk of Obesity Let s take a closer look at some examples Understanding genomic risk factors and how they relate ultimately to Leptin vs other pathways helps us understand how we can intervene in Obesity (even if we don t know someone s exact genomics).

Let s Go Inside the Hypothalamus: MC4R Melanocortin 4 Receptor Most common cause of genetic obesity in children Variants decreases number of functional melanocortin 4 receptors Modulated by Leptin These are found in the hypothalamus and help regulate satiety and appetite through the leptin and ghrelin pathways. MC4R low activity causes hunger. MC4R high activity causes satiety.

Variants in MC4R SYMPTOMS OF MC4R Variants: Constant hunger (hyperphagia), lack of satiety Childhood obesity Leads to snacking behaviors Weight gain Emotional eating Significant in all ethnicities

Let s now work outward from MC4R

Pathway of Hunger: Agouti Leads to Decreased MC4R 1) Agouti gene: Ghrelin (hunger hormone) stimulates AGRP (Agouti Receptor Peptide) and releases the Agouti peptide that turns off MC4R HUNGER 2) Leptin binding to AGRP neurons inhibits the release the Agouti Related Peptide (turns off appetite) 3) AGRP co localizes with the orexigenic (hunger) neuropeptide Y (NPY) in arcuate nucleus of the hypothalamus (another gene that helps you regulate appetite) Pharmaceuticals 2010, 3, 3494 3521; doi:10.3390/ph3123494

EPIGENETICS IS THE TURNING ON AND OFF OF GENES BY ENVIRONMENTAL FACTORS: Proper Methylation and diet can turn off the obesity Treated with proper nutrients downregulates obesity Choline Betaine Folate Agouti Peptide Pathway is classic for showing epigenetics of Obesity. OBESE MOUSE was choline, folate and betaine deficient. Both mice are from same litter and are Agouti gene mice. Citation: Gao X, Wang Y, Randell E, Pedram P, Yi Y, Gulliver W, et al. (2016) Higher Dietary Choline and Betaine Intakes Are Associated with Better Body Composition in the Adult Population of Newfoundland, Canada. PLoS ONE 11(5): e0155403. https://doi.org/10.1371/journal.pone.0155403

BPA in Plastics also can Affect Agouti Pathway BPA from plastics reduces methylation of the Agouti protein gene (higher expression). Methylation turns off genes High BPA and low methylation has been associated with adult onset obesity, diabetes and tumorigenesis. BPA is still in 16,000 foods on American shelves and detected in 93% of individuals Trasande L, Attina TM, Blustein J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA. 2012;308:1113 1121.

Melanocortin 4 is also involved in sleep and light cues as part of regulating metabolism MC4R helps minimize wide fluctuations of glucose on a circadian rhythm The mechanism for how sleep disruption leads to metabolic disorders is unclear, but reduced sleep is correlated with low Leptin and high Ghrelin

Pathway #2 to Hunger: Proopiomelanocortin (POMC ) also Leads to MC4R 1. Leptin binds to POMC gene and stimulates it to stimulate MC4R and suppresses appetite 2. Disruption of the POMC gene results in an obesity phenotype in mouse and humans. POMC variants cause low levels of POMC and thus you don t properly stimulate MC4R in the presence of leptin (and remain hungry). 3. POMC also cause low levels of ACTH and thus adrenal issues. Tends to be associated with fair skin and red hair. Rare cause of obesity. Pharmaceuticals 2010, 3, 3494 3521; doi:10.3390/ph3123494

Leptin Receptor Variants: One of the Most Common Genetic Traits Contributing to Adult Obesity LEPR SNPs are highly correlated with adult obesity and have almost 3 fold increased risk. These SNPs either correlate to missense variants (abnormal receptors with less affinity for leptin) vs less receptors (i.e. promotor issue etc.).

Leptin Receptor Variants: Business Class Mice and Humans... Leptin resistance is a huge component of obesity and thus leptin unable to create satiety. Causes Leptin insensitivity Causes hyperphagia. BUSINESS CLASS MICE

Leptin Receptor Contribution to Obesity Leptin resistance can be caused not only by genetics but also by diet. Diet induced leptin resistance will trigger increase energy intake and weight gain. ***Leptin resistance can occur even in the absence of elevate circulating leptin levels due to receptor abnormalities.**** BBB resistance happens early on even with mild obesity (saturation of the receptors since less receptors don t get enough message)

Leptin Receptor Dietary Contributions Sat Fat, Fructose and Sucrose 1) Decreased leptin sensitivity is triggered with 12g/day or more saturated fat consumption 1) In rat models consumption of high fat diet induces leptin resistance in 3 5 d. 2) High fructose diet triggers leptin resistance and hyperphagia (which is via a different reversible pathway of decreasing AMPK phosphorylation) 3) High sucrose diet also confers leptin resistance

Leptin Paradox: Obesity Generally is Leptin Resistance Leptin is expressed by adipocytes: both its expression and its secretion are highly correlated with body fat and adipocyte size i.e. higher fat stores should = higher leptin Since leptin makes you feel full it might seem like obese people have less leptin However, obesity is not characterized by leptin deficiency but rather by elevated leptin levels The inability of such elevated leptin levels to alter obesity in these individuals = leptin resistance

Leptin Genes Contributing to Leptin Resistance LEP is Leptin gene approx 1.4 2x higher risk SNPs associated with this gene cause increased risk of obesity. Given in obese individuals leptin levels are almost 3x/ higher theory is inability of leptin to enter the cerebral spinal fluid to reach the hypothalamus regions that regulate appetite. May be due to defective leptin shape Also Leptin binds to crp and this prevents crossing BBB

Now let s transition to STAT3; Another protein that interacts with Leptin but also inflammation. LEP (2.0 2.5 X risk) LEPR (2.9 X risk) STAT3 (1.9 2.2 X risk) MC4R (1.3 X risk) PCSK1 (1.34 X risk)

STAT3: Focus on the Waist Line Signal Transducer and Activator of Transcription 3 : NORMALLY: STAT3 signaling is required for leptin downregulation of food intake STAT3 regulates blood sugar levels by suppressing hepatic glucose production Particularly associated with abdominal obesity. Interacts with interleukin 6 (IL 6).

STAT3: Transcription Factor: The more SNPs the More Abdominal Obesity But only with SFAs Catherine M. Phillips; Dietary Saturated Fat Modulates the Association between STAT3 Polymorphisms and Abdominal Obesity in Adults, The Journal of Nutrition, Volume 139, Issue 11, 1 November 2009, Pages 2011 2017, https://doi.org/10.3945/jn.109.110635

STAT3 is a Second Messenger for the Leptin Receptor In Obesity: SNPs appear to decrease function. STAT3 acts as a second messenger in the arcuate nucleus and activates the leptin signaling pathway. Loss of function studies leads to increased weight gain, increased insulin resistance.

STAT3 and Saturated FAT: Lower sat fat to help decrease abdominal obesity. Saturated fat intake WAS PREDICTIVE of increased waist circumference. PUFAs and MUFAs and Omega did not modulate genetic associations.

FTO Fat Mass and Obesity associated Protein REGULATOR of Other Genes Ranges from 1.3 2.8 X risk/variant Dozens of SNPs that increase risk Many are linked, so if a patient has one, they likely have others magnifying their risk Appears to code for an enzyme that demethylates RNA and turns genes on and off throughout the genome, including those in the hypothalamus and adipose tissue

FTO Regulate STAT 3 and the Mitochondria Get internalized and increase respiration STAT3 is regulated by FTO (via phosphorylation) (FTO reduces STAT3 phosphorylation by leptin by 1.9 fold) Silencing STAT3 blocks Leptin induced FTO effects Bravard et al. Cell Communication and Signaling 2014, 12:4

Different snps have been found to affect genes in a variety of locations including the hypothalamus and adipose tissue Role in adipocyte differentiation and fat storage (white vs brown fat) As one of the best studied obesity genes, there are some subtle snp specific diet and exercise interventions Let s get a closer look: FTO (Fat Mass and Obesity Associated Protein)

Examples of Dietary Interventions and Relationships Seen with FTO Some SNPs associated with meat and dairy cravings and other sorts of binge eating and emotional eating. Higher risk of Diabetes as well BMI increase only with HIGH SAT FAT DIET and FRIED FOODS EXERCISE: Highly beneficial Mediterranean Diet was beneficial Supplements that may help with cravings and binge eating Ashwagandha Honokiol/ magnolol

Examples of FTO snp Specific Interventions: Most of the studied snps for FTO show greater weight loss with a Mediterranean diet Some variants affect food choice rather than quantity with a preference for higher caloric food (meats and cheeses). Larder, R. et al. (2011). Where to go with FTO? Trends in Endocrinology & Metabolism, 22(2), 53 59. Razquin, C. et al. (2010). A 3 year intervention with a Mediterranean diet modified the association between the rs9939609 gene variant in FTO and body weight changes. International Journal of Obesity, 34:266 272.

FTO Role of Exercise is Not Just About Calories Lack of physical activity has been shown to increase risk even when corrected for caloric expenditure. Studies have shown that for some snps, moderate physical activity can decrease risk between 36 75% even when corrected for caloric expenditure Reddon, H. (2016). Physical activity and genetic predisposition to obesity in a multiethnic longitudinal study. Nature Scientific Reports, 6:1 10.

One Last Family: Obesity Genes Known to Target Fatty Acid Synthesis, Storage or Metabolism: FABP2 APOA2 DLK1 PLIN1 PLIN6 MAF Let s look at one up close:

FABP2: Fatty Acid Binding Protein Works in small intestine affecting uptake, metabolism and transport of long chain fatty acids FABP2 increases fat absorption (omega 6) Individuals with the FABP2 variant have a 2 fold greater affinity for the long chain fatty acids =hyperabsorbers Stimulates TNF alpha An increase in omega 6 fatty acids = increases transcription of TNF α, an inflammatory cytokine which results in inflammation, decreased fatty acid breakdown and increased insulin resistance Which affects inflammation and Insulin resistance

FABP2 Fatty Acid Binding Protein 2 FABP2

FABP2 Can Double to Quadruple risk of Obesity most significant in Chinese Odds ratio of 2.63 for one snp (rs1799883) Additive odds ratio 2 alleles 4.16 FABP2 indirectly increases inflammation, modifies FA metabolism and increases hunger through higher absorption of omega 6 FA in intestine

FABP2 rs1799883 Associated with insulin resistance Causes lower leptin levels after a high monounsaturated fat diet in obese, nondiabetic patients= hungry Higher absorption omega 6 Higher post prandial triglycerides Higher cholesterol

FABP2 and Other Obesity Gene Interactions: LEP FABP2 impacts ability of LEP to regulate food intake by downregulating leptin TNFa FABP2 increases TNFa resulting in inflammation, the inhibition of lipid metabolism and increasing synthesis of FA APOA2 important component of HDL that is reduced with FABP2; TNF FABP2 Omega 6 GLUT4 GLUT4 insulin transporter, reduce stability in presence of more Omega 6 LEP APOA

Interventions for FABP2: Ideal Fat Needs Differ Eat less linoleic /Omega 6 Containing foods If obesity is due to FABP2 (Chinese) High omega 6 eat less of these

Interventions for FABP2: Typical Asian Diet Diet high is seafood, fish, pork, coconut milk, vegetables, rice Supplementation with 1.8g fish oil was shown to help weight loss Ideal diet was moderate fat not low fat (30% fat, 15% protein, 55% carbs)

Aerobic exercise has been shown to be more effective than walking in reducing obesity indicators (BMI, blood parameters etc.) Aerobic Exercise and FABP2 Effects Ala54Thr polymorphism of FAB2 on obesity index and biochemical variable response to aerobic exercise training Tae Kyung Han (2013) Journal of Exercise and Nutritional Biochemistry 17 (4):209 217.

APOE2 Apolipoprotein A2 Works on the Other Side of the Scale HDL related apolipoprotein Affects triglyceride metabolism Correlates with Ghrelin concentrations Snp correlated with reduced transcription (lower activity) Appears to increase risk by modifying ghrelin concentrations= individuals are hungrier and eat more food Risk can be removed with a diet low in saturated fats

APOA2 rs5082 1.84 X risk only if ate high saturated fat diet In fact no association was detected in the low SAT FAT group (OR=0.81) HDL related apolipoprotein The variant reduced APOA2 and affects triglyceride transport and metabolism Diet very low in saturated fat (10 20g/day) is most success for weight control Associated with behaviors known to sabotage weight loss: meal planning and skipping meals Smith, C. E. et al. (2012). Apolipoprotein A II polymorphism: relationships to behavioural and hormonal mediators of obesity. International Journal of Obesity, 36(1): 130 136.

ApoA2 Diet Recommendations Very low saturated fat has been shown to be most helpful This is 10 20 grams/ day Generally avoid fat from mammals completely as mammal products (beef, pork, cheese, butter, sour cream) are 37 71% saturated fat as opposed to avocados, olive oil, seeds, nuts which are 9 18% saturated fat Coconut oil is very high saturated fat (tropical plants/ solid fats)

Fat cells secrete more than 50 hormones and signaling molecules Adipokines One More Thing to Mention: Inflammation Modulates Obesity: Adipose tissue from lean individuals secrestes antiinflammatory signals (TGFβ, IL10, IL4, IL13, IL1 receptor agonist etc). Obese individuals release inflammatory cytokines proinflammatory cytokines (TNF α, IL6, leptin, resistin, angiotensin II and plasminogen activator inhibitor 1) Pro inflammatory adipokines modulate insulin resistance

Inflammation in Obesity Drives Insulin Resistance Obesity is characterized by chronic, low to moderate level inflammation in nearly all tissues Inflammation probably drives most of the negative consequences of weight gain Inflammation has been shown to cause insulinresistance

Insulin also is meant to suppress appetite.. Insulin resistance thwarts this

Additionally There are Obesity Genes Known to Target Insulin Synthesis and/or Sensitivity: ENPP1 SH2B PCSK1

Which diet is best? High Fat? Low Fat? More PUFAs?MUFAs? It varies

Fatty Acids are Powerful Moderators of Gene Activity Type of dietary fat can influence gene transcription. Genetic risk for some gene variants can be changed by modifying the types of dietary fat consumed. With most genetic variants, saturated fat is associated with increased hunger and obesity compared to plant fats, higher in omega 3 and PUFA, MUFAs

Which diet is best? High Fat? Low Fat? More PUFAs?MUFAs? It varies But because so many of the obesity SNPs work on the Leptin/Leptin Receptor/MC4R/STAT3 pathway if you don t have genomics a good place to start is LOW SATURATED FAT unless Asian

Assuming Hypothalamic Contributors and Leptin Resistance? Keep saturated fat low (<12g/day) Keep total dietary fat low (<83g/day) Domínguez Reyes, T. et al. (2015). Interaction of dietary fat intake with APOA2, APOA5 and LEPR polymorphisms and its relationship with obesity and dyslipidemia in young subjects. Lipids in Health and Disease, 14.

Keep Vegetables and Fiber High

If Insulin Resistance likely also will have to lower carbohydrates Insulin levels can be measured. High Insulin is likely insulin resistant

Another Thing to Counsel Patients Artificial Sweeteners Preliminary Data Known for a while that there is a correlation between artificial sweeteners and BMI Preliminary data indicate that artificial sweeteners are modifying transcription of obesity genes Increasing glucose transporter molecules Increasing adipogenesis and fat deposition

Obesity is Complex Genetics risk variants do not occur in isolation = complex genetic landscape Diet gene diet interactions can affect risk Sleep affects leptin Level of physical activity has shown to impact risk independent of its effects on BMR or net calories

How to Discuss Obesity with Patients

If you have snps and genomics great But if you don t

I like to talk about Hibernation Phenomenon For Caucasian patients in particular that came from Europe Food was less abundant in winter (feast vs famine) Advantage to having hunger triggered during hunting season (fall when animals are grown and migrating) Saturated fat (animal meat) triggering storage of fat signals Thus Leptin/ LEPR snps are very common as there was survival advantage to being able to store fat well.

For Patients from Other Parts of the World Saturated fats would be plentiful during hunting season. Survival advantage if stored fat during time when animal fat plentiful. This helped with survival during droughts or famines

NOW Hyperphagia is problematic given year round food supply. Portion control (remember MC4R) Diet: Stress What YOU Eat and How Much Much less saturated fat / Mediterranean diet is often good option.

Explain Leptin Resistance: You have plenty of stored fat but the brain is not getting the signal This creates hyperphagia Dietary studies show worse with saturated fats

Remind patients how exercise can alter their gene expression Exercise tells the brain you are on the move and need energy for your muscles so it is not time to divert energy to stomach but also alters expression of a number of genes. Particularly important for FTO which is common contributor to Obesity It is not just about burning calories.

The End Thanks for Listening Questions? Sharon.MD@resilienthealth austin.com