Fatty Acids — Mini-Lecture 1

Introduction

• Series of four mini-lectures explores fatty acids and ketoacidosis in Type $1$ diabetes.
• Current (first) lecture focuses exclusively on fatty acids as fuels.

Fatty Acids as an Energy-Rich Fuel

• Complete aerobic oxidation of the saturated fatty acid palmitate ( $16$ carbons, $0$ double bonds) yields roughly $130\;ATP$.
• Requirement for molecular oxygen ( $O_2$ ) ⇒ oxidation must occur in mitochondria.

Basic Chemical Structure

• General formula: carboxylate head $\left(\;COO^-\;\right)$ + repeating $CH<em>2$ units + terminal methyl $\left(\;CH</em>3\;\right)$.
• Carbon-naming conventions:
  • Numeric: carboxyl carbon $=1$, next $=2$, etc.
  • Greek: first methylene $=\alpha$, second $=\beta$ … final carbon $=\omega$.

Even-Numbered Chains

• Natural fatty acids almost always have an even number of carbons (assembled in $2$-carbon units during biosynthesis).

Saturated vs. Unsaturated

• Saturated = no double bonds (e.g.
  palmitate).
• Unsaturated = one or more C=C double bonds.
  • Each double bond can exist in cis or trans configuration.

Cis vs. Trans Geometry

• Cis: incoming and outgoing carbon chains lie on same side of the double bond, producing a visible kink.
• Trans: chains are on opposite sides; molecule remains essentially straight (no kink).
• In nature, cis is overwhelmingly predominant; multiple cis bonds ⇒ multiple kinks.

Physical Consequences of Unsaturation

• Kinking disrupts tight packing ⇒ lowers melting temperature.
• Therefore unsaturated fatty acids are liquids at body temperature, increasing accessibility to metabolic enzymes.

Transport Forms Within the Body

1. Non-esterified ("free") fatty acids

• Circulate bound to serum albumin.

2. Esterified fatty acids

• To glycerol ⇒ triacylglycerols (TAGs, triglycerides).
• To cholesterol ⇒ cholesterol esters.
• Both travel inside lipoprotein particles.

Triacylglycerol (TAG) Architecture

• Glycerol backbone + $3$ ester linkages $\left( C{-}O{-}C{=}O \right)$ + $3$ fatty acids.

Cholesterol Ester Architecture

• Single fatty acid esterified to the hydroxyl of cholesterol.

TAGs as Energy Stores

• TAGs dominate dietary fat and adipose stores.
• Energy density arises from the attached fatty acids.

Body-Composition Example (DEXA Scan)

• Dual-energy X-ray absorptiometry of presenter:
  • Total body mass ≈ $71$ kg.
  • Body-fat percentage ≈ $24.8$\%.
  • Fat mass ≈ $18$ kg.
• Demonstrates substantial endogenous energy reserve (“how much lard do I have?”).

Mobilization of Fat from Adipocytes

• Adipocyte = lipid droplet full of TAGs + thin cytoplasmic rim.
• Hormone-Sensitive Lipase (HSL) performs lipolysis at oil–water interface.
  • Reaction:
  $\text{TAG} + 3\;H_2O \xrightarrow[\text{HSL}]{} \text{Glycerol} + 3\;\text{Fatty Acids} + 3\;H^+$
  • Releases $3$ free fatty acids and $3$ protons per TAG.

Hormonal Regulation

• Activation:
  • Adrenaline (epinephrine) via $\beta$-adrenergic receptors.
  • Glucagon via the glucagon receptor.
• Inhibition:
  • Insulin down-regulates HSL.

Fate of Circulating Fatty Acids

• Free fatty acids bind albumin and travel to energy-demanding tissues.
• Detailed metabolic fate (β-oxidation, ketone formation, etc.) will be explained in the next mini-lecture.

Key Take-Home Messages

• Fatty acids are highly energy-dense, yielding up to $130\;ATP$ per molecule (palmitate).
• Cis-unsaturation lowers melting point, keeping fats fluid and metabolically accessible at $37$ °C.
• Transported either as albumin-bound free fatty acids or in esterified forms within lipoproteins.
• Adipose TAGs are mobilized by HSL, stimulated by glucagon and adrenaline, suppressed by insulin.
• Released fatty acids constitute a central fuel pool—critical in contexts such as Type $1$ diabetes and impending ketoacidosis (topics for subsequent lectures).