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Unlock your guides8.3 Obesity and metabolic disorders
4 min read•august 16, 2024
, a condition of excessive body fat, wreaks havoc on metabolism. It turns fat tissue into a hormone factory, pumping out substances that mess with and blood pressure. This sets the stage for a host of health problems.
The body fights back, but it's a losing battle. Inflammation takes hold in fat cells, making insulin less effective. This snowballs into a chain reaction, affecting the liver, muscles, and pancreas. It's a perfect storm for metabolic mayhem.
Obesity and Metabolic Disorders
Defining Obesity and Its Metabolic Impact
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Figure 1: Excess visceral and ectopic fat accumulation is causally related to the development of ... View original
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Frontiers | The Impact of Obesity and Lifestyle on the Immune System and Susceptibility to ... View original
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Frontiers | Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome View original
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- Obesity involves excessive body fat accumulation measured by a Body Mass Index (BMI) of 30 or higher
- Adipose tissue functions as an endocrine organ in obesity
- Secretes various and inflammatory mediators
- Contributes to systemic metabolic dysfunction
- Obesity strongly associates with
- Cluster of disorders including , hypertension, and
- correlates more strongly with metabolic disorders than subcutaneous fat
- Particularly abdominal fat
- Chronic low-grade inflammation in adipose tissue links obesity to various metabolic disorders
- Obesity-induced alterations in adipokine production contribute to metabolic disorders
- Increased levels
- Decreased levels
Adipose Tissue Function and Inflammation
- Adipocyte hypertrophy and hyperplasia occur in obesity
- Lead to altered adipokine production
- Increase pro-inflammatory cytokine secretion (, )
- Chronic activation of inflammatory pathways contributes to insulin resistance
- NF-κB pathway
- JNK pathway
- Adipose tissue inflammation impacts multiple metabolic organs
- Liver (hepatic insulin resistance)
- Skeletal muscle (impaired glucose uptake)
- Pancreas (β-cell dysfunction)
- Macrophage infiltration in adipose tissue exacerbates inflammation
- M1 macrophages predominate in obese adipose tissue
- Release pro-
Insulin Resistance in Type 2 Diabetes
Mechanisms of Insulin Resistance
- Insulin resistance involves cells becoming less responsive to insulin
- Leads to impaired glucose uptake and utilization
- Excess adipose tissue in obesity releases factors interfering with insulin signaling
- Free fatty acids
- Inflammatory cytokines (TNF-α, IL-6)
- Insulin resistance affects multiple organs
- Liver (increased )
- Muscle (decreased glucose uptake)
- Adipose tissue (impaired lipid storage)
- Molecular mechanisms of insulin resistance include
- Impaired insulin receptor substrate (IRS) phosphorylation
- Decreased PI3K/Akt pathway activation
- Increased activity of protein tyrosine phosphatases (PTP1B)
Progression to Type 2 Diabetes
- Chronic insulin resistance leads to compensatory
- Pancreas produces more insulin to maintain normal blood glucose levels
- occurs over time
- Pancreas fails to produce sufficient insulin to overcome insulin resistance
- Results in
- Progression from insulin resistance to type 2 diabetes involves complex factors
- (, genes)
- Environmental factors (diet, physical inactivity)
- and exacerbate beta-cell dysfunction and insulin resistance
- Chronic hyperglycemia damages β-cells ()
- Elevated free fatty acids impair insulin secretion and action
Metabolic Consequences of Obesity
Dyslipidemia in Obesity
- Obesity-related dyslipidemia characterized by
- Elevated
- Decreased
- Increased small, dense
- Insulin resistance promotes hepatic triglyceride synthesis and VLDL secretion
- Contributes to dyslipidemic profile
- Impaired activity in adipose tissue
- Reduces triglyceride clearance from circulation
- Increased hepatic lipase activity
- Enhances HDL catabolism, lowering HDL levels
- changes in obesity
- Increased apoB (found in atherogenic lipoproteins)
- Decreased apoA-I (major protein in HDL)
Non-Alcoholic Fatty Liver Disease (NAFLD)
- strongly associates with obesity and insulin resistance
- Characterized by excessive fat accumulation in the liver
- Spectrum of NAFLD ranges from to (NASH)
- Can progress to and
- Obesity-induced alterations in adipokine production contribute to NAFLD
- Decreased adiponectin (anti-inflammatory, insulin-sensitizing)
- Increased leptin (pro-inflammatory)
- Key metabolic abnormalities in obesity-related NAFLD
- Increased hepatic
- Impaired
- "Two-hit hypothesis" explains NAFLD progression
- First hit: lipid accumulation sensitizes the liver
- Second hit: inflammatory insults promote disease progression
- Insulin resistance in NAFLD
- Increases lipolysis in adipose tissue, elevating circulating free fatty acids
- Promotes hepatic lipid accumulation and inflammation
Mechanisms of Obesity-Related Disorders
Cellular Stress and Dysfunction
- Endoplasmic reticulum (ER) stress links obesity to metabolic disorders
- Activates (UPR)
- Contributes to insulin resistance and inflammation
- in obesity
- Impairs cellular energy metabolism
- Increases (ROS) production
- Impaired autophagy in obesity contributes to cellular dysfunction
- Reduces clearance of damaged organelles and protein aggregates
- Exacerbates ER stress and inflammation
- Increased oxidative stress in obesity
- Results from imbalance between ROS production and antioxidant defenses
- Damages cellular components (lipids, proteins, DNA)
Systemic and Molecular Mechanisms
- Obesity-induced alterations in contribute to metabolic dysfunction
- Changes in ("leaky gut")
- Altered production of metabolites ()
- play a role in obesity-related metabolic disorders
- changes in metabolic genes
- affecting gene expression
- Potential for transgenerational transmission of metabolic risk
- dysregulation in obesity
- Key regulator of cellular metabolism and growth
- Contributes to insulin resistance and metabolic dysfunction
- Adipose tissue expandability hypothesis
- Limited capacity for healthy adipose tissue expansion
- Ectopic fat deposition when capacity is exceeded
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