Nutritional Pathophysiology of Obesity and its Comorbidities

A Case-Study Approach

Susan Ettinger

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128030134
• eBook ISBN: 9780128030349
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Nutritional Pathophysiology of Obesity and Its Comorbidities: A Case-Study Approach challenges students and practitioners to understand the role of nutrients within the pathophysiology and development of disease, specifically those diseases which develop as a result of obesity. Through a case-based approach, the author presents complex clinical scenarios that require multiple treatment strategies, including targeted diet modification as an adjuvant to medical therapy. The book is divided into 9 modules and 5 appendices each of which covers aspects of obesity and its comorbidities. Within each module, a case is detailed with relevant history, laboratory and physical data, and follow-up information. Each case is followed by a resource section which delineates current understanding of the pathophysiology of the condition, as well as the actions of nutrients and food components shown to modify these processes. A "further readings" section cites current supporting clinical and basic literature as well as published guidelines. - Explores how obesity is a key player in the pathophysiology of many diseases, including diabetes mellitus, chronic renal failure, hypertension, and atherosclerosis - Integrates current understandings of the molecular mechanisms of nutrient action on the processes of disease development and treatment - Presents students and early practitioners with complex clinical scenarios through a practical case-based approach

Chapter 1

Obesity and Metabolic Syndrome

Abstract

This chapter presents an obese woman who requests consultation about losing weight. Resources include discussion on biological systems that control energy balance including neuroendocrine signaling pathways, gut microbiota, and genetics. Integration of nutrient utilization controlled by master sensors, is detailed together with cellular adaptations such as autophagy, lipid droplet formation senescence that compensate for nutrient dysregulation. Adipose tissue depots are distinguished with respect to their differentiation patterns, structure, secretory function, and dysregulation in obesity and the metabolic syndrome. The influence of the gut microbiota on obesity is explored. Links to intestinal permeability, endotoxemia, and immune modulation on energy balance, as well as influences of microbial secretions in regulation of intestinal gluconeogenesis and neuronal signaling that impacts food intake regulation are examined. Published recommendations as well as experimental evidence in support of targeted diet modulation strategies for achieving and maintaining optimal body weight are presented, together with discussion of areas in need of future research.

Keywords

Obesity; metabolic syndrome; microbiota; adipose tissue; neuroendocrine signaling; diet

Chief Complaint (Typical Patient)

A 41-year-old African-American woman requested consultation about losing weight. She was somewhat overweight as a child, has a history of dieting throughout adolescence and adulthood, and has gotten successively heavier, especially after the birth of her four children ages 8, 9, 12, and 15.

Medical History

• Prediabetes with mild hyperglycemia (fasting blood glucose levels 115–125 mg/dL).

• Workups for other endocrine abnormalities have been negative in three previous examinations.

• The patient has been hospitalized four times for vaginal childbirth; no gestational diabetes.

• She has no known history of gallbladder disease, allergy, or hyperlipidemia.

• Although her husband noted that she snores at night, she does not wake from snoring, nor does she fall asleep at odd times during the day.

• Skin: no history of rashes or unusual skin pigmentation, stretch marks, or skin tags;

• Neurologic: no headaches, tremors, seizures, or depression;

• Endocrine: normal menstrual cycle, no abnormal heat or cold intolerances;

• Cardiovascular: no hypertension, heart disease, orthopnea, or dyspnea;

• Joints: no swelling, heat, or redness.

Family History

The patient lives with her husband (44 years) and children (8, 9, 12, and 15 years). She works as a social worker; her husband is a plumber. The patient reports no history for diabetes, although many of her first-degree relatives have been diagnosed with hypertension and hyperlipidemia. Her father died at 68 years of a heart attack. Her mother (65 years) has hypertension and hyperlipidemia controlled with medication.

Physical Examination

• General appearance: obese woman in no acute distress; no cushingoid features.

• Exam: nonpalpable thyroid; no hirsutism or striae; no dorsal, cervical, or supraclavicular fat; no acanthosis nigricans; no edema.

• Vital signs: temperature: 98.4°F; HR 88 bpm; BP 145/90 mmHg.

• Anthropometric data:

• Height 5′4″ (163 cm); weight 265 lb (120.2 kg); BMI 45.5 kg/m²; adjusted IBW 81.2 kg (calculation from http://www.globalrph.com/ibw_calc.cgi/);

• Waist circumference 46 inches (106.7 cm);

• Triceps skinfold 8 cm (80 mm);

• Mid arm muscle circumference 28 cm (280 mm).

Laboratory Data

• Blood chemistries: within normal limits.

• Complete blood count: within normal limits.

• Thyroid function test: normal.

	Patient’s value	Normal values
• Fasting serum glucose	115 mg/dL	65–100 mg/dL
• Hgb A1c	5.9%	<5.5%
• Potassium	3.8 mEq/L	2.8–6.2 mEq/L
• Total serum cholesterol	230 mg/dL	<200 mg/dL
• Serum triglycerides	200 mg/dL	<150 mg/dL
• Serum iron	52 µg/dL	50–170 µg/dL

Diet History

• The patient does not smoke and drinks 1–2 glasses of wine or beer with dinner about every 2 days.

• The patient drinks two or three cups of coffee a day.

• Throughout her life, the patient has tried a number of weight-loss diets with 20–40 pounds of weight loss on each occasion. Each time the weight returned within a year, and she typically leveled off at 10–15 pounds more than before.

• The patient walks 2–3 blocks to and from the subway each day, but does not have regular planned exercise.

• The patient’s highest lifetime weight was 285 pounds, she is now at 265 pounds. Her low adult weight was 140 pounds when she lost ~60 pounds for her wedding 20 years ago.

A 24-hour Dietary Recall

Breakfast

• Coffee (2 cups) with skim milk (1/2 cup);

• Cereal (3/4 cup) with a banana and (1/2 cup) skim milk.

Lunch

• Grilled chicken fillet (3 oz) sandwich with lettuce and tomato on a roll (no mayo);

• Diet coke.

Afternoon Snack

• Large coffee with Splenda and coffee creamer.

Dinner

• Eggplant Parmesan with low-fat mozzarella;

• Steamed broccoli rabe with lemon;

• Green salad with low-fat ranch dressing (~1/4 cup);

• Red wine (1 glass).

After Dinner

• Fat-free sorbet (1 cup);

• 5 low-fat chocolate chip cookies (1.5 inches each).

Intake	kcal 1602	Protein 47 gm
Requirements	kcal 1935^a	Protein 64.96 (Adj. IBW×0.8×kg)

^aHarris Benedict calculations using 1.2 activity factor. http://www-users.med.cornell.edu/~spon/picu/calc/beecalc.htm/.

Resources

Obesity is not a personal failing. In trying to lose weight, the obese are fighting a difficult battle. It is a battle against biology, a battle that only the intrepid take on and one in which only a few prevail (Friedman, 2003).

1.1 Food and Organic Life

The laws of thermodynamics apply in living organisms as in the physical environment. To survive, an organism must regulate its supplies of energy and substrate to repair and replace body systems that continually undergo entropy and degradation. Food intake is the only way in which substrate can be provided, thus in a very real sense, we are what we eat. In order to free up time to go about the activities of daily living, food intake is, necessarily, episodic, thus most organisms consume meals at intervals throughout the day. To assure that the food taken in provides an adequate supply of substrate to maintain life, organisms have elaborated complex systems of central and peripheral sensors that monitor intake of food, passage of its metabolites through the intestinal tract, absorption, transport in the circulation, utilization, and storage for later use. Mediators such as leptin and gut hormones trigger an integrated web of neural, endocrine, paracrine, and other signals that regulate energy expenditure and body composition to maintain homeostasis as illustrated in Figs. 1.1–1.3 below.

Figure 1.1 Nutrient sensing and downstream actions.
AMPK activation controls metabolism of glucose and lipids to increase catabolic pathways that provide substrate for ATP generation and to decrease biosynthetic pathways that utilize energy. The mammalian target of rapamycin complex 1 (mTORC1) is integrated with AMPK. It promotes growth and anabolic processes in response to amino acid availability. Note that although two mTOR complexes exist, only mTOR 1 is sensitive to amino acids. Stimulatory interactions are indicated with ↓, and inhibitory interactions are indicated with ⊥.
GLU4, glucose transporter type 4; CPT1, carnitine palmitoyltransferase-1; TAK1, TGF-β-activated kinase 1; LKB1, liver kinase B1 (a key AMPK activator tumor suppressor); CAMKKβ, calmodulin-dependent protein kinase kinase β; ACC, acetyl CoA carboxylase; PFK2, phosphofructokinase 2; GS, glycogen synthase; HDACs, histone deacetylases; CRTC2, CREB-regulated transcription coactivator 2; FOXO, forkhead box protein O; CREB, cAMP response element-binding protein; ULK, UNC-51-like kinase; FIP200, 200 kDa FAK family kinase-interacting protein; ATG, autophagy-related; PI3K, phosphoinositide 3-kinase; IRS1, insulin receptor substrate 1; PTEN, phosphatase and tensin homolog; PDK1, 3-phosphoinositide-dependent protein kinase 1; TSC1/2, tuberous sclerosis 1/2; Rheb, Ras homolog enriched in brain; v-ATPase, vacuolar H⁺-adenosine triphosphatase; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; S6K, ribosomal S6 kinase; Ragulator, a protein complex responsible for lysosomal recruitment and activation of Rag GTPases; PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1α; PPARγ, peroxisome proliferator-activated receptor-γ; SREBP, sterol regulatory element-binding protein; HIF, hypoxia-inducible factors. Reproduced from Yuan, H.-X., Xiong, Y., et al., 2013. Nutrient sensing, metabolism, and cell growth control. Mol. Cell 49 (3), 379–387—Science Direct.

Figure 1.2 Autophagy.
Cellular homeostasis requires that biosynthetic and degradation processes be tightly coordinated to respond to changing environmental conditions. Autophagy adjusts cellular content to the changing physiological needs. Note that mTORC1 localizes to the lysosome (red circle) to detect newly released amino acids. Reproduced from Todde, V., Veenhuis, M., et al., 2009. Autophagy: principles and significance in health and disease. Biochimica et Biophysica Acta (BBA)—Mol. Basis Dis. 1792 (1), 3–13 (Todde et al., 2009)—Science Direct.

Figure 1.3 Leptin and gut hormones integrate multiple systems to maintain energy homeostasis.
Leptin released from adipocytes, mediators from the gut, and other neuronal and hormonal signals are integrated through the brain to regulate food intake, energy expenditure, mood, and behavior as well as other systems that maintain homeostatic functions in response to changing environmental and physiological settings. Reproduced from van der Klaauw, A.A., Farooqi, I.S., 2015. The hunger genes: pathways to obesity. Cell 161 (1), 119–132—Science Direct.

As the organism grows, escapes predation, reproduces, and ages, the signals are modulated and body composition altered in response to substrate need (Wells, 2006). The vast literature exploring this integrated system has been reviewed extensively (Mayer and Thomas, 1967; Weigle, 1994; Rosenbaum et al., 1997; Simpson and Raubenheimer, 2005; Friedman, 2014; van der Kla...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Foreword
• Foreword
• Preface
• Chapter 1. Obesity and Metabolic Syndrome
• Chapter 2. The Obese Gunshot Patient: Injury and Septic Shock
• Chapter 3. Type I Diabetes and Celiac Disease
• Chapter 4. Type II Diabetes, Peripheral Neuropathy, and Gout
• Chapter 5. Cardiopathy and Congestive Heart Failure
• Chapter 6. Atherosclerosis and Arterial Calcification
• Chapter 7. Diabetic Nephropathy, Chronic Kidney Disease
• Chapter 8. Asthma and Obesity
• Chapter 9. Osteoporosis and Fracture Risk
• Essentials I. Life in an Aerobic World
• Essentials II. Heavy Metals, Retinoids, and Precursors
• Essentials III. Nutrients for Bone Structure and Calcification
• Essentials IV. Diet, Microbial Diversity, and Gut Integrity
• Essentials V. Nutrition Support in Critically Ill Patients,
• Index