Adipose Biology and Chronic Disease Risk

What are the two main functions of adipocytes?

1. lipid (TAG) storage and mobilization (which tend to be highly regulated by hormones)

2. endocrine functions

Describe some of the endocrine functions of adipocytes (2).

• adipokines: bioactive proteins and signaling molecules released by adipose (fat) tissue that regulate metabolism, inflammation, and energy balance

  • ex: adiponectin and leptin

• cytokines: many are produced by adipocytes

  • ex: TNFa, IL-1, IL-6

What is visceral adiposity?

fat w/n the abdominal area

• metabolically active

What is subcutaneous adipose?

adipose that is more readily distributed throughout the body

What is hypertrophy?

enlargement

• overweight (BMI 25 - 29.9) and moderate obesity (BMI 30 - 34.9) are characterized by adipocyte hypertrophy

What is hyperplasia?

increase in number

• extreme obesity (BMI > 40) is characterized by both hyperplasia and hypertrophy

What happens when adipocytes undergo hypertrophy or hyperplasia?

tend to attract immune cells amongst the tissue, causing inflammation

Describe the characteristics associated with adipose tissue in lean individuals.

• insulin sensitive

• absence of inflammation

• secrete adiponetctin, IL-4, IL-10 (which help to maintain insulin sensitivity)

Describe the characteristics associated with adipose tissue in overweight/obese individuals.

• insulin resistant

• MCP-1 chemokine recruits more macrophages which secrete

  • pro-inflammatory cytokines (IL-1beta, TNFa, etc)

  • secrete more chemokines

• hypertrophy and hyperplasia

• increase in leptin (and increased can cause our brain to be desensitized to it, making us unaware when we are full) and decrease in adiponectin

• hypoxia (body tissues do not get enough oxygen to function properly)

• ROS

• promotion of lipolysis and release of FFA

What is ectopic fat?

storage of TG in tissues or locations not usually associated with significant adipose tissue accumulation such as liver, muscle, renal, and pancreas (have a lipid overflow and they need somewhere to go)

What is the issue with ectopic fat?

• the metabolic inflammation that occurs in excessive adipose tissue with the help of the immune cells, will begin to occur within these different tissues (sub-clinical inflammation)

• results in metabolic changes in the liver, muscle, renal function, pancreas, etc.

  • causes insulin resistance in multiple tissues including the liver and increased glucose output by liver (bc think that we are starving)

  • beta cell dysfunction in pancreas, causing changes in insulin output

• overall has health implications as it increases the risk of type II diabetes and endothelial dysfunction (vascular dysfunction), high BP, and CVD

Describe a way in which immune cells (such as macrophages) communicate with adipocytes in adipose tissue.

• adipocytes have cross talk with macrophages and these macrophages overproduce pro-inflammatory cytokines such as TNF-a

• TNF-a cytokines can act (paracrine, endocrine, autocrine, etc) to interact with adipocytes inducing NFkB pathway to make more cytokines

• additionally cytokine binding on adipocyte contributes to inhibition of insulin signaling pathway

  • causes insulin resistance and lipolysis (release of FFA)

    • FFA released from adipocyte can bind to another TLR4 receptor on the adipocyte and macrophage, inducing MORE NFkB activation

What do the adipocytes of obese individuals overproduce?

adipokines

• except adiponectin (used for regulation)

Why is NFkB referred to a lot?

it is a central pathway to inflammatory metabolic responses

Why can’t NFkB just be inhibited so that we don’t have inflammation?

bc it contributes to a lot of things alongside inflammation

better off modulating diet

Describe this image:

Describe obesity stats worldwide.

43% of adults are overweight and 16% obese

• doubled from 1990

Describe obesity stats in the US.

40.3% of adults are obese and 21.1% of youth are obese

Where is obesity more prevalent?

• low income households

• varies with racial and ethnic status (black, hispanic, and white)

How many out of the top ten leading causes of death are diet related?

4/10

• 45% of cardiometabolic deaths are related to suboptimal intake of dietary components and patterns

What are the three contributors to obesity?

1. behavior and energy balance

2. genetics (typically polygenic)

3. environment

obesity is multi-factorial

What is energy balance influenced by?

interaction of genetic and epigenetics; metabolic, hormonal, physiological factors, environment, behavior, lifestyle, gut microbiome, living situation, chronic stress, sleep pattern etc.

What are two different models explaining why there is more obese/overweight people?

1. Energy Balance Model (EBM)

2. Carbohydrate-Insulin Model (CIM)

Characteristics associated with the Energy Balance Model (EBM).

obesity is caused by highly palatable foods and obesogenic environments

• disrupt food intake signaling, resulting in a positive energy balance

Characteristics associated with the Carbohydrate-Insulin Model (CIM).

obesity is caused by alterations in fuel partitioning

• favors storage (ex: via fructose pathway) due to high intake of rapidly digestible carbohydrates

• rapid high insulin promotes adipose storage

What are the two categories of mechanisms that help to regulate our food intake/energy balance?

1. homeostatic mechanisms

2. non-homeostatic mechanisms

What are non-homeostatic mechanisms that help to regulate our food intake/energy balance?

• hedonics (taste, smell, emotional memory)

• stress (cortisol)

What are two types of homeostatic mechanisms that help to regulate our food intake/energy balance?

1. adipokines (long term signals)

2. gut hormones and physical (short term gut-brain axis signals, tells us the presence of food and nutrient metabolism)

What are two adipokines?

1. leptin

2. adiponectin

Role of leptin.

synthesized by adipocytes

• signals to reduce appetite and increase energy expenditure

• obesity: leptin production in increased but neurons in brain are resistant to its actions

Role of adiponectin.

synthesized by adipocytes

• signals to improve insulin sensitivity

• obesity: adiponectin production is decreased

What gut hormone signals hunger?

ghrelin

• synthesized by stomach

What three hormones can signal satiety?

1. CCK

2. GLP-1

3. Insulin

Characteristics of CCK.

• stimulated by protein and fat

• secreted by I cells in proximal small intestine

• helps to regulate the release of pancreatic enzymes and bile

Characteristics of GLP-1.

• produced by L cells in the distal small intestine (ileum)

• regulates pancreatic alpha and beta cells and insulin response

What is the difference between hunger and appetite?

hunger

• physical need for food

• response to low blood glucose

• physical sensation in stomach

appetite

• desire for food with or without hunger

• includes sensory and emotional aspects and is tied into brain reward systems

• can be dysregulated in eating disorders

What is the influence of the gut microbiota on obesity?

• gut microbiota can produce neuroactive peptides (ex: serotonin) and SCFA which can affect host metabolism and appetite

• gut microbiota profiles and ecology differ in obesity (which is associated with increase capacity for energy harvest from dietary intake)

• can play a role in metabolic disorders

  • colonization of germ free mice w/ gut microbiota from obese human resulted in increased total body fat compared to lean gut microbiota

• NOT the only determinant it is a lot more complex

  • changed in gut microbiota was determined by high fat diet NOT obesity state

How do you define a disease?

it is a pathological condition of a part, organ, or system of an organism resulting from various causes, and characterized by identifiable signs and symptoms, with potential adverse health consequences and outcomes

What are the three general features of disease?

1. recognizable etiologic agents

2. consistent anatomical alterations, related to pathophysiology

3. identifiable signs and symptoms, features of impaired health

Is obesity considered a disease?

Yes

its a chronic and relapsing disease, not something that can be fixed by a quick diet

What are the different organizations that consider obesity a disease? (9)

Describe health insurance coverage as it relates to obesity.

• medicare/medicaid will cover some obesity related treatments (ex: behavioral therapy and bariatric surgery if necessary) HOWEVEr, it does not routinely cover anti-obesity medications

• large variations in what treatments insurance companies will reimburse for when considering obesity treatment, and many will pay for treating conditions caused by obesity but not the underlying obesity condition

What are the different body fat percentages associated with obesity in men vs women?

• males: > 25%

• females: > 33%

Definition of obesity.

having an excess of adipose tissue or a very high amount of body fat in relation to lean body mass

What are three indirect measures of obesity?

1. waist circumference

2. waist:hip rati

3. body mass index

Describe waist circumference in relation to obesity.

men: >102 cm (> 40in)

women: > 88 cm (> 35in)

Describe waist-hip ratio in relation to obesity.

disease risk increase when WHR is > 0.95 in men and > 0.8 in women

Describe BMI in relation to obesity.

high risk > 30

BMI = weight in kg/(height in m squared)

Interpret BMI levels.

BMI does not take into account body fat distribution or muscle mass

Do we directly track BMI for children and teens?

not really

• use a BMI-for-age tracking chart in order to ensure that they track with rate of growth and development

Describe the different weight classifications in terms of percentiles for BMI-for-age.

What type of fat is a predictor of risk for obesity-related diseases?

abdominal fat, especially visceral fat in that region

• terms “apple” shaped

• central or upper body distribution

• android distribution

• central/visceral adiposity is strongly and consistently related to metabolic risk of chronic disease

What type of fat stores is less of a risk for obesity-related diseases?

lower body or gluteofemoral distribution

• gynoid distribution

• “pear” shape

What has a higher metabolic risks, visceral adiposity or lack of moderate to vigorous physical activity?

visceral adiposity has more

• technically both impact metabolic risk

What proportion of obese youth have the “adult” co-morbidities of obesity?

1/3