Obesity: An Introduction and What We Can Do (Part 2)

Fat Cells (Adipocytes)

During weight gain, fat cells (adipocytes) grow in size, a process known as hypertrophy. Once these cells reach their storage capacity, the body begins creating new fat cells, called hyperplasia. These cells undergo epigenetic changes that “remember” being enlarged, which often drives rapid weight regain even after dieting.

The Cellular Mechanics of Fat Storage

Hypertrophy vs. Hyperplasia

Initially, existing fat cells swell to store excess caloric energy. In severe or prolonged obesity, the body recruits stem cells to create new fat cells.

Hypertrophy

When energy intake exceeds expenditure, existing fat cells increase in size as they store excess lipids.

Hyperplasia

In severe obesity, the body recruits new fat cells from stem cells (including those in bone marrow) to manage excess energy storage, increasing the total number of fat cells.

Cellular “Memory”

Research shows that fat cells and their precursor cells retain epigenetic marks of past obesity. This causes them to store nutrients more readily and predisposes them to rapid regrowth, making sustained weight loss difficult.

Lipid Turnover

In individuals living with obesity, lipid turnover inside fat cells decreases. The cells absorb lipids efficiently but release them slowly, resulting in net tissue growth.

Why Fat Becomes Harmful

Chronic Inflammation

As fat cells expand, they outgrow their blood supply and begin producing pro-inflammatory proteins such as TNF-α and IL-6. This leads to low-grade systemic inflammation.

Metabolic Dysfunction

Inflamed fat tissue struggles to store lipids effectively, causing “spillover” into the liver and muscles. This significantly increases the risk of:

• Type 2 diabetes

• Insulin resistance

• Cardiovascular disease

Fat Distribution

Visceral fat, stored around internal abdominal organs, is metabolically more active and dangerous than subcutaneous fat stored under the skin.

Causes of Obesity

Genetics

Single-gene mutation (monogenic) obesity is rare and occurs in less than 1% of cases. Most identified mutations are linked to the leptin-melanocortin pathway and may be present in up to 6% of individuals with severe childhood-onset obesity.

Environment

Poverty, social factors, work profiles, and lifestyle conditions are significant contributors.

Energy Balance

Food intake is converted into energy in the body. Since people are not constantly eating, energy is stored to meet the body’s demands.

Resting metabolic rate (RMR), the number of calories the body burns at rest just to survive, accounts for approximately 70% of total energy expenditure and is closely correlated with fat-free mass.

The remaining energy expenditure comes from:

• Thermic effect of food

• Physical activity

Specific hormonal and neurological pathways regulate these domains and may play an important role in obesity.

Gastric Sensory Functions

The stomach provides important information regarding meal quantity and controls the rate at which food enters the small intestine through a process called gastric emptying (GE).

Gastric Distention

Regardless of caloric content, stomach distention provides negative feedback in food intake regulation.

Distention:

• Decreases appetite

• Reduces food intake

• Correlates with tolerated gastric volume and body weight

Gastric Motor Function

Gastric emptying controls the transit of food from the stomach to the intestine and influences signaling processes related to hunger and satiety.

Research shows:

• Accelerated gastric emptying is associated with obesity

• Rapid GE is linked with increased hunger

• Altered satiety contributes to weight gain

Enteric and Adipose Hormones

When food enters the duodenum, nutrients stimulate enteroendocrine cells to release hormones that regulate appetite and stomach motility.

Some hormones stimulate appetite (orexigenic), while others promote satiety (anorexigenic).

Leptin and Ghrelin in Appetite Regulation

Leptin and ghrelin are two key hormones with opposing functions.

Ghrelin

• Stimulates appetite

• Activates orexigenic neurons

• Increases food intake

Leptin

• Suppresses appetite

• Reduces food intake

• Promotes satiety

• Increases energy expenditure

In many individuals with obesity, high leptin levels fail to produce the expected response. This condition is called leptin resistance and remains a major challenge in obesity treatment.

Adipose Tissue

Leptin

Leptin is primarily produced by adipocytes and closely correlates with white adipose tissue mass.

Weight loss and fasting reduce leptin levels. Leptin also influences:

• Thermogenesis

• Energy expenditure

• Neuroendocrine signaling

Adiponectin

Adiponectin is produced exclusively by adipocytes and plays a major role in:

• Insulin sensitivity

• Lipid regulation

• Fatty acid oxidation

Lower adiponectin levels are associated with:

• Obesity

• Visceral fat accumulation

Diet and weight loss can increase adiponectin concentrations.

Central Regulation

The central nervous system receives signals from:

• Autonomic pathways

• Hormones

• Circulating nutrients

Important hormones include:

• Leptin

• CCK

• GLP-1

• PYY3-36

Multiple brain regions integrate these signals to regulate appetite and energy balance.

Obesity Pathophysiology and Morbidity

Positive energy balance leads to excess calorie storage in adipose tissue. Excess adiposity contributes to:

• Metabolic dysfunction

• Chronic inflammation

• Immune changes

• Mechanical stress

Major obesity-related comorbidities include:

• Cardiovascular disease (CVD)

• Type 2 diabetes mellitus (T2DM)

• Cancer

Dyslipidemia and Inflammation

Obesity is associated with systemic and local inflammation.

Studies show increased secretion of inflammatory cytokines such as:

• IL-6

• TNF-α

Obesity-related adipose tissue also demonstrates:

• Increased macrophage infiltration

• Increased T-cell activity

• Immune dysregulation

These changes contribute to insulin resistance and cardiometabolic disease.

Insulin Resistance

The inflammatory environment associated with obesity disrupts insulin signaling through multiple mechanisms.

Inflammatory cytokines:

• Alter insulin receptor signaling

• Reduce glucose uptake

• Promote further inflammation

Changes in insulin signaling affect:

• Skeletal muscle

• Liver

• Glucose homeostasis

Animal studies demonstrate that suppression of inflammatory pathways can protect against insulin resistance.

Metabolically “Healthy” and “Unhealthy” Obesity

Individuals with obesity and metabolic dysfunction are considered metabolically unhealthy.

Indicators include:

• Dyslipidemia

• Hypertension

• Insulin resistance

• Elevated inflammatory markers

Approximately 30% of individuals with obesity may be considered metabolically healthy.

However, metabolic dysfunction significantly increases future cardiovascular risk.

Central Adiposity

Central obesity is strongly associated with:

• Cardiovascular disease

• Metabolic syndrome

• Insulin resistance

Research shows waist circumference predicts:

• Hypertension

• Type 2 diabetes

• Dyslipidemia

More accurately than BMI alone.

Central obesity is also associated with worse outcomes in critical illness.

Sarcopenic Obesity

Sarcopenic obesity is characterized by:

• Obesity

• Reduced muscle mass or muscle function

It may occur with or without central adiposity.

Contributing factors include:

• Physical inactivity

• Hormonal changes

• Chronic inflammation

• Myocellular changes

Diagnosis is typically based on:

• Muscle mass measurements

• Strength testing