Changes in cellular processes in Obesity

Obesity and overweight not only affect the external aesthetic of a patients but dramatically effects the processes of the billions of cells in the human body. Originally, adipose tissue was thought to be inert and composed solely of adipocytes. However, over the past several years, other cellular populations have been discovered within adipose tissue that are affected by obesity.  Whilst cells within the visceral and subcutaneous fat are effected other cells throughout the body suffer insulin resistance and general inflammation showing how excess weight effects the individual holistically.

1. Adipose Tissue Dysfunction

In obesity, adipose tissue undergoes hypertrophy and hyperplasia. Enlarged adipocytes secrete adipokines and pro-inflammatory cytokines like TNF-α and IL-6. This leads to chronic inflammation (adipose tissue inflammation or adiposopathy) and is linked to insulin resistance.¹

2. Insulin Resistance

Insulin resistance is a physiological condition in which the body’s cells, such as muscle, fat, and liver cells, do not respond effectively to the hormone insulin. This results in a reduced ability to regulate blood sugar (glucose) levels and can lead to various metabolic and health problems.

• Insulin is a hormone produced by the pancreas that plays a crucial role in regulating blood sugar. It facilitates the uptake of glucose by cells, allowing them to use it for energy or store it as glycogen (in the liver and muscles) or fat. Insulin also helps suppress the release of glucose from the liver.³

Consequences of Insulin Resistance:

• When cells become insulin resistant, several metabolic consequences occur: a. Hyperinsulinemia: The pancreas produces more insulin to compensate for the reduced cellular response. b. Elevated Blood Sugar: With insulin resistance, blood sugar levels remain higher than normal. c. Impaired Glucose Tolerance: Insulin resistance often progresses to impaired glucose tolerance and, if left uncontrolled, can lead to type 2 diabetes. d. Dyslipidemia: Insulin resistance is associated with abnormal lipid profiles, including elevated triglycerides and reduced high-density lipoprotein (HDL) cholesterol.^{4, 5}

Causes of Insulin Resistance:

• The exact causes of insulin resistance are multifactorial and involve genetic, lifestyle, and environmental factors. Common contributors to insulin resistance include: a. Obesity: Excess fat, particularly abdominal fat, is strongly associated with insulin resistance. b. Sedentary Lifestyle: Lack of physical activity can exacerbate insulin resistance. c. Genetics: Family history can increase the risk of insulin resistance. d. Diet: Diets high in refined sugars and saturated fats can contribute to insulin resistance.^6,7

3. Inflammation

Obesity-associated cellular inflammation, also known as chronic low-grade inflammation, is a hallmark of obesity and is closely linked to various metabolic and cardiovascular complications. This inflammatory state involves changes in cellular processes and the secretion of pro-inflammatory molecules from adipose tissue and other cells. Here is an overview of obesity-associated cellular inflammation with references for further reading:

Cellular Inflammation in Obesity:

1. Adipose Tissue Inflammation:
   • In obesity, adipose tissue undergoes significant changes. Enlarged adipocytes (fat cells) produce and release pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1).² These adipokines contribute to local and systemic inflammation⁸.
2. Macrophage Infiltration:
   • Obese adipose tissue attracts immune cells, particularly macrophages. These infiltrating macrophages can secrete additional inflammatory cytokines, intensifying inflammation in adipose tissue^{9, 10}.
3. Endoplasmic Reticulum (ER) Stress:
   • Obesity-induced ER stress is a contributor to inflammation. Increased fat accumulation can lead to ER stress, which triggers the unfolded protein response (UPR) and may further promote inflammation and insulin resistance^{11, 12}.
4. Systemic Effects:
   • The inflammation in obese adipose tissue is not limited to the adipose tissue itself. Pro-inflammatory cytokines and adipokines are released into the bloodstream, leading to systemic inflammation that can affect other organs and tissues^{13, 14} .

Obesity-associated cellular inflammation is a key contributor to insulin resistance, metabolic syndrome, and other obesity-related health issues. Understanding the cellular and molecular mechanisms underlying this inflammation is crucial for developing interventions to manage and prevent the adverse health consequences of obesity.

4. Hormonal Dysregulation

Leptin, an adipose-derived hormone, regulates appetite and energy expenditure. In obesity, leptin resistance occurs. Ghrelin, another hormone that stimulates hunger, may also be dysregulated^{15, 16}. These hormones have been targeted by pharmaceutical companies looking to treat overweight an obesity. We will discuss these hormones in more detail later in the course.

References:

1. Trayhurn, P., & Wood, I. S. (2005). Adipokines: inflammation and the pleiotropic role of white adipose tissue. British Journal of Nutrition, 92(3), 347-355.
2. Hotamisligil, G. S. (2006). Inflammation and metabolic disorders. Nature, 444(7121), 860-867.
3. DeFronzo, R. A., & Abdul-Ghani, M. A. (2011). Preservation of beta-cell function: the key to diabetes prevention. Journal of Clinical Endocrinology & Metabolism, 96(8), 2354-2366., G. M. (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 37(12), 1595-1607.
4. Reaven, G. M. (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 37(12), 1595-1607
5. Samuel, V. T., & Shulman, G. I. (2012). Mechanisms for insulin resistance: common threads and missing links. Cell, 148(5), 852-871.
6. Hulman, S., & Tabak, A. G. (2017). The burden of prediabetes and diabetes. In S. Colagiuri & S. M. Kim (Eds.), Textbook of Diabetes (5th ed., pp. 1-12). Wiley.
7. Sesti, G., & Antonelli, A. (2019). Cardiometabolic risk and insulin resistance. Journal of Endocrinological Investigation, 42(11), 1233-1240.
8. Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., … & Hotamisligil, G. S. (2003). Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation, 112(12), 1821-1830.Rosenbaum, M., & Leibel, R. L. (2014). Leptin: a molecule integrating somatic energy stores, energy expenditure and fertility. Trends in Endocrinology & Metabolism, 25(3), 117-125.
9. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante Jr, A. W. (2003). Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation, 112(12), 1796-1808.
10. Lumeng, C. N., & Saltiel, A. R. (2011). Inflammatory links between obesity and metabolic disease. Journal of Clinical Investigation, 121(6), 2111-2117.
11. Ozcan, U., Cao, Q., Yilmaz, E., Lee, A. H., Iwakoshi, N. N., Özdelen, E., … & Tabas, I. (2004). Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 306(5695), 457-461.
12. Hotamisligil, G. S. (2010). Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell, 140(6), 900-917.
13. Wellen, K. E., & Hotamisligil, G. S. (2003). Obesity-induced inflammatory changes in adipose tissue. Journal of Clinical Investigation, 112(12), 1785-1788.
14. Shoelson, S. E., Lee, J., & Goldfine, A. B. (2006). Inflammation and insulin resistance. Journal of Clinical Investigation, 116(7), 1793-1801.
15. Cummings, D. E., Purnell, J. Q., Frayo, R. S., Schmidova, K., Wisse, B. E., & Weigle, D. S. (2001). A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes, 50(8), 1714-1719.
16. Rosenbaum, M., & Leibel, R. L. (2014). Leptin: a molecule integrating somatic energy stores, energy expenditure and fertility. Trends in Endocrinology & Metabolism, 25(3), 117-125.