Obesity and Insulin Resistance Regulation

Regulators of Obesity and Insulin Resistance

• Imbalance in food intake and energy expenditure leads to increase in body weight and obesity
• When storage capacity of WAT becomes saturated, fat accumulates in peripheral organs
• Excess lipids in non-oxidative pathways result in production of reactive toxic lipid species, leading to tissue-specific damage and lipotoxicity

Adipose Tissue as an Endocrine Organ

• Adipose tissue releases hormones called adipokines
• Adipokines:
  • Carry information to the brain about fuel stores and other tissues
  • Leptin and adiponectin are adipokines
  • Regulate fuel metabolism and feeding behavior to maintain body mass
  • Imbalance can result in life-threatening diseases

Key Hormones Regulating Energy Balance

• Leptin:
  • Appetite-suppressing hormone
  • Sent from adipose tissue to the brain
  • Decreases appetite
• Neuropeptide Y:
  • Orexigenic hormone (appetite-stimulating hormone)
  • Sends signals to eat
  • Levels rise during starvation
  • Inhibited by leptin and insulin
• ɑ-melanocyte-stimulating hormone:
  • Anorexigenic hormone (appetite-suppressing hormone)
  • Sends signals to stop eating
  • Release stimulated by leptin and insulin
• Ghrelin:
  • Short-term orexigenic hormone secreted in the stomach
  • Increases hunger
  • Associated with Prader-Willi syndrome

Adiponectin and PPARs

• Adiponectin:
  • Made by adipose tissue
  • Increases insulin sensitivity in organs
  • Affects fatty acid metabolism and carbohydrate metabolism in liver and muscle
• PPARs (peroxisome proliferator-activated receptors):
  • Alter gene expression for fat and carbohydrate metabolism
  • PPARɣ, PPARɑ, PPARδ

Microbiome and Obesity

• Microbiome in the gut influences obesity
• Microbes function as endocrine glands affecting metabolism, feeding behavior, and body mass
• Obese and lean individuals have different gut microbial flora

Type 1 Diabetes

• Caused by autoimmune reaction where the body's immune system attacks insulin-producing beta-cells in the pancreas

Glycerol and Glyceroneogenesis

• Glycerol from fats enters either gluconeogenesis or glycolysis
• Glyceroneogenesis:
  • Abbreviated version of gluconeogenesis in liver and adipose tissue
  • Uses pyruvate, alanine, glutamine, or other substances from the CAC as precursors for glycerol-3-phosphate

Carnitine-Acylcarnitine Shuttle

• Transports fatty acids with +14 carbons
• Acyl-carnitine/carnitine transporter belongs to group E7 enzyme class
• Requires 2 ATPs

Catabolism of Fatty Acids

• Lipolysis:
  • Place of action: TAGs in adipocytes, in the cells cytosol and lipid droplets
  • Hormones glucagon and epinephrine trigger mobilization of stored TAGs
  • Lipases cleave fatty acids from the glycerol backbone of TAGs
• Fatty acid oxidation divided into 3 stages:
  1. Oxidative conversion of two-carbon units into acetyl-CoA via beta-oxidation
  2. Oxidation of acetyl-CoA into CO2 through the CAC
  3. Repeated ingestion of fructose can lead to liver disease, kidney disease (treatment: total elimination of fructose from the diet)

Lipids

• Functions:
  • Energy storage
  • Cell membrane structure
  • Cofactors for enzymes
  • Signaling molecules
  • Steroid hormone synthesis
  • Antioxidants
  • Pigments
  • Insulation
  • Protection
  • Fat-soluble vitamin transport and absorption
• Types of lipids found in food and synthesized by the body:
  • TAGs
  • Cholesterol
  • Phospholipids
  • Free fatty acids
  • White adipose tissue (WAT) and brown adipose tissue (BAT)
• Characteristics of WAT and BAT:
  • WAT: large spherical cells, function in fuel storage and release
  • BAT: smaller cells, multiple lipid droplets, function in thermogenesis