Ch 23- Obesity & Disorders of Nutrition

• There are three classifications of adipose tissue: white, brown, and beige

White Adipose Tissue (WAT)

• Most abundant adipose tissue in body
• Originates from connective tissue and is stored in visceral (central) and subcutaneous (peripheral) areas, muscle groups, and bone marrow
• Contains white adipocytes, each with a single triglyceride fat droplet or vacuole
• Visceral white adipocytes primarily store fat as triglycerides in the form of very-low-density lipoprotein (VLDL) that is produced from hepatic and dietary sources
• Regulates energy homeostasis through the secretion of adipokines
• Low nutritional state stimulates the sympathetic nervous system
• Epinephrine/norepinephrine is released, which activates hormone-sensitive lipase
• Lipolysis occurs in white adipose tissue releasing free fatty acids and glycerol into circulation
• Adipose tissue provides insulation, mechanical support, and is the body's major energy reserve
• It is an endocrine organ in which adipocytes secrete adipokines
• Adipocytes are fat storing cells that secrete adipokines
• Cell-signaling proteins function like hormones, having autocrine, paracrine, and endocrine actions which regulates energy homeostasis
• Adipokines are biologically active substances synthesized by white adipose tissue.
• They control food intake, energy expenditure, lipid storage, insulin sensitivity, immune and inflammatory responses, coagulation, fibrinolysis, angiogenesis, fertility, vascular homeostasis, and BP regulation
• Stores excess energy in the form of triglycerides (triglycerol): Synthesizing triglycerides from glucose
• Mobilizes stored energy in the form of free fatty acids (FFAs) and glycerol
• Location include visceral (central) and subcutaneous (peripheral) stores, muscle groups, and bone marrow
• Pancreatic insulin inhibits lipolysis by activating insulin receptors in adipocytes; with obesity, adipocytes become resistant to insulin lipolysis
• Positive energy balance leads to excess fat storage in mature white adipocytes, causing hypertrophy and adipogenesis (hyperplasia, formation of new fat cells from preadipocytes)
• Chronic positive energy balance can overwhelm adipogenesis, which results in fat storage depending only on hypertrophy
• Key functions: insulation and energy storage
• Obesity, caused by excess visceral adipose tissue, increases the risk for metabolic complications like insulin resistance and type 2 diabetes
• Obesity causes chronic, low-grade inflammation in WAT: Macrophages, lymphocytes (proinflammatory CD8+ T cells), neutrophils, and mast cells infiltrate enlarged adipocytes and release inflammatory cytokines
• Macrophages shift from anti-inflammatory (M2) to proinflammatory (M1) phenotypes
• Causes inflammatory state through increased leptin and resistin, decreased adiponectin, and escalated eicosanoid production
• Inflammation and accelerated lipolysis lead to insulin resistance, metabolic syndrome, and obesity complications such as type 2 diabetes, cardiovascular disease, and cancer

Brown Adipose Tissue (BAT)

• Derived from muscle tissue and contains lipid droplets or vacuoles and is rich in mitochondria that contain iron, giving it a brown color
• Exposure to cold, activation of SNS/catecholamines, and triiodothyronine (T3) stimulates brown adipose tissue to rapidly generate heat
• Heat generation is done through UCP1 (uncoupling protein 1 - nonshivering thermogenesis)
• UCP1 promotes mitochondrial respiration and dissipates chemical energy as heat from increased glucose and free fatty acid oxidation
• Occurs 50x faster than white adipose tissue and protects against obesity and metabolic syndrome
• Neonates generate body heat from brown adipose tissue primarily located in the interscapular and perirenal regions
• Adults have visible brown adipose tissue (UCP1) on PET scans, which is common in lean individuals located in the neck, supraclavicular, axillary, paravertebral and perineal regions
• Minimally produces leptin and adiponectin, having little effect on appetite and satiety
• Amount is inversely related to BMI and age
• Variation of brown adipose tissue and “brite” adipocytes may participate in natural regulation of weight reduction
• Brown adipose tissue participates in non-shivering thermogenesis through lipid oxidation
• Its distinct brown color is attributed to its high mitochondrial density
• Critical for heat generation and lipid oxidation
• Proposed that brown adipose tissue diminishes with aging
• PET/CT studies: brown adipose tissue is viable and functional in human adults

Beige Adipose Tissue (bAT)

• Located within white adipose tissue, particularly in subcutaneous fat depots
• Contains multiple mitochondria and UCP1, but not as much as brown adipose tissue
• Its contribution is thermogenesis
• Emerges within white adipose tissue with chronic exposure to cold, with exercise, and with energy expenditure
• Known as "beiging" of white adipose tissue that disappears when ambient temperature is elevated
• Chronic exposure to cold causes white adipose tissue transdifferentiation to beige adipose tissue (thermogenic)
• Warm adaptation causes beige adipose tissue to revert to white adipose tissue
• Exercise promotes browning of white adipose tissue
• Leptin and insulin together promote beige adipose tissue, increasing energy expenditure and weight loss
• Diminishes with obesity

Bone Marrow Adipose Tissue

• Found in all bones, but greater in long bones
• Releases adipokines with autocrine, paracrine, and endocrine effects
• Increase levels = osteoporosis

Arcuate Nucleus (ARC)

• Located in hypothalamus, regulates food intake and energy metabolism by balancing the opposing effects of two sets of neurons
• AgRP/NPY neurons produce agouti-related protein (AgRP) and neuropeptide Y (NPY)
• These promote appetite, stimulate eating, and decrease metabolism (anabolic)
• Known as orexigenic neurons
• These are stimulated by molecules called orexins
• POMC/CART neurons synthesize pro-opiomelanocortin-producing peptide and cocaine-and-amphetamine-regulated transcript (CART)
• They suppress appetite, inhibit eating, and increase metabolism
• Known as anorexigenic neurons
• These are stimulated by molecules called anorexins

Orexins (appetite Stimulants)

• Neuropeptide Y (NPY)
• Melanin-concentration hormone (MCH)
• Agouti-related protein (AgRP)
• Ghrelin
• Galanin
• Orexins A & B
• Endocannabinoids
• Cortisol

Anorexins (appetite suppressants)

• Leptin
• Insulin
• Cholecystokinin (CCK)
• Glucagon-like peptide 1 (GLP-1)
• Peptide YY (PPY)
• Corticotropin-releasing factor (CRF)
• Urocortin (A CRF satiety signaling hormone)
• Cocaine- and amphetamine-regulated transcript (CART)
• Alpha-melanocyte-stimulating hormone
• Bombesin
• Serotonin
• Calcitonin

Methods to estimate/measure adipose tissue to screen for obesity

• Anthropometric measurements (weight, height, and circumferences of various body diameters) e.g. waist-to-hip ratios and waist circumference
• Skinfold thickness (measured via skinfold calipers)
• Ultrasound to measure peripheral body fat
• Bioelectric impedance and underwater hydrostatic weighing to calculate total body fat
• DEXA scans (dual energy x-ray absorptiometry) the ONLY method for directly measuring total body fat
• Body mass indices (BMI) based on height, weight, age, gender, and ethnicity in adults
• BMI> than 25 kg/m2 is overweight
• BMI> than 30 kg/m2 is obesity
• BMI charts = ages 2 to 20 years
• Waist circumference provides additional insight into disease risk assessment and body water distribution

Malnutrition

• Lack of nourishment from inadequate calories, protein, vitamins, or minerals caused by:
• Improper diet
• Alterations in digestion or absorption
• Chronic disease
• Combination of such factors

Starvation

• Reduction in energy intake leading to weight loss, split into three types:
• Therapeutic Short Term: initial rapid weight loss motivates dieters
• Therapeutic Long Term: facilitates rapid weight loss in morbidly obese persons
• Pathologic Long Term: related to poverty; chronic cardiovascular, pulmonary, hepatic and digestive system disease, malabsorption syndromes, HIV infection, and cancer

Short term starvation (extended fasting)

• Duration is several days of total dietary abstinence or deprivation
• The body responds with mechanisms to protect protein mass
• For 4 to 6 hours after the last meal, the body uses glucose from recently ingested carbohydrates
• Glycogen in the liver is converted to glucose through glycogenolysis (splitting of glycogen into glucose) which takes about 4 to 8 hours to peak
• Gluconeogenesis (glucose formation from noncarbohydrate molecules) begins
• Both glycogenolysis and glycogenesis occur in the liver
• Both processes deplete stored nutrients & cannot meet the body's energy needs indefinitely
• Proteins are catabolized to a minimal degree for synthesizing glucose

Long term starvation

• Period after several days of dietary abstinence and eventually causes death
• Absolute depravation of food causes marasmus or protein-energy malnutrition (loss of muscle mass & body fat depletion)
• Kwashiorkor is protein deprivation in the presence of carbohydrate intake, which causes loss of muscle mass with sustained body fat
• Marmasmic Kwashiorkor is a combo of chronic energy deficiency and chronic or acute protein deficiency and inadequate micronutrients (edematous, severe, childhood malnutrition)

Cachexia (cytokine induced malnutrition)

• Physical wasting with loss of weight and muscle atrophy, fatigue, and weakness.
• Mediators (TNF-a, interferon-y, IL-1, IL-6) and increased catabolic response causes cachexia of advanced cancer
• Cancer, AIDS, TB, and other chronic diseases can contribute to cachexia
• Differs from food deprivation starvation as the body cannot adjust; a healthy body adjusts to it by slowing the metabolic rate

Long-term starvation characteristics

• Decreased dependence on gluconeogenesis
• Increased use of ketone bodies as cellular energy
• Decreased insulin levels
• Increased glucagon levels, cortisone, epinephrine, and growth hormones
• Lipolysis in adipose tissue releases fatty acids, which supply energy to cardiac and skeletal muscle cells and ketone bodies
• Fatty acid oxidation meets most of the energy needs of cells while some glucose is still needed as fuel for brain tissue
• Supply of adipose tissues is depleted and proteolysis begins
• Muscle and visceral protein breakdown is the last to try to supply energy for life
• Causes severe electrolyte balance and loss of renal, pulmonary and cardiac function leading to death

Treatments for starvation & malnutrition

• Starvation: manage inadequate ingestion of appropriate nutrients
• Medically induced starvation: maintain patient in a ketotic state until desired adipose tissue is lysed
• Starvation by chronic disease, long term illness, malabsorption syndromes, or chronic eating disorders: enteral or parenteral nutrition
• Refeeding Syndrome can occur upon initiation of parenteral/enteral nutritional therapy and can be life threatening; start feedings at about 20 kcal/kg/day

Anorexia of aging

• A decrease in appetite or food intake in older adults that can occur in illness-free individuals and in the presence of adequate facilities
• Caused by multiple age-related changes
• Reduced energy needs, waning hunger, diminished senses of smell and taste, decreased saliva production, altered gastrointestinal satiety control mechanisms and the presence of comorbidities
• Central aging: decreased orexigenic signals (decreased ghrelin or ghrelin resistance and reduced NPY/NPY receptors) and increased anorexigenic signals (decreased leptin, insulin, PYY and CCK)
• The consequences may be loss of appetite and diminished food intake
• Chronic low-grade inflammation with elevated cytokines can delay gastric emptying and decrease motility in the small intestine
• Risk factors include physical and mental functional impairments, loneliness, medications, social isolation, and abuse or neglect
• Complications malnutrition, physical frailty, mitochondrial dysfunction, reduced regenerative capacity, increased oxidative stress, and imbalanced hormonal problems
• Support strategies include improved food access and appearance, dental and eye care, and social interaction