5.4 Tissue-Specific Metabolism, Body-Mass Regulation & Obesity

Why the MCAT Tests Metabolism Organ by Organ

The AAMC content outline lists tissue-specific metabolism, hormonal regulation of fuel metabolism and obesity and regulation of body mass as explicit subtopics of Content Category 1D. Passages almost never ask you to recite a pathway in isolation; they hand you a physiological scenario (a fasting runner, a poorly controlled diabetic, a leptin-deficient mouse) and expect you to predict flux through pathways you already know. The unifying idea is that every tissue runs the same chemistry but expresses a different subset of enzymes and transporters, and that difference determines who donates fuel and who consumes it.

Metabolic Division of Labor Across Five Key Tissues

1. Liver — the Central Fuel Distributor

The hepatocyte is the only cell type that can simultaneously perform gluconeogenesis, ureagenesis and ketogenesis at high capacity.

• Glucose sensing: Hepatocytes use glucokinase (hexokinase IV), a high-$K_m$ ($\approx 10\text{ mM}$), non-product-inhibited isozyme, so hepatic glucose uptake rises steeply only after a carbohydrate meal.
• Glucose export: The liver expresses glucose-6-phosphatase, which strips the phosphate from glucose-6-phosphate so free glucose can leave through GLUT2. Skeletal muscle lacks this enzyme entirely.
• Nitrogen disposal: Only the liver runs a complete urea cycle, converting the ammonia generated by amino acid deamination into urea for renal excretion.
• Ketone export: The liver makes acetoacetate and $\beta$-hydroxybutyrate but lacks succinyl-CoA:3-ketoacid CoA transferase (thiophorase), so it cannot consume the ketones it produces.

2. Skeletal Muscle — the Selfish Consumer

• Muscle glycogen (~400 g in a 70 kg adult, versus ~100 g in liver) is a private reserve; without glucose-6-phosphatase, glucose-6-phosphate is committed to glycolysis inside the myocyte.
• Resting and endurance muscle prefers fatty acid $\beta$-oxidation; burst activity relies on creatine phosphate (a few seconds) and then anaerobic glycolysis.
• Muscle exports carbon as lactate (Cori cycle) and nitrogen as alanine (glucose–alanine cycle), both of which the liver reconverts to glucose at ATP cost to the liver.
• GLUT4 in muscle and adipose is insulin-dependent; exercise recruits GLUT4 to the membrane through an AMPK-dependent, insulin-independent route.

3. Brain — the Obligate Glucose User That Learns to Use Ketones

• Consumes roughly 120 g glucose/day and about 20% of resting oxygen despite being ~2% of body mass.
• Long-chain fatty acids are albumin-bound and do not cross the blood–brain barrier in useful quantities, so the brain cannot substitute fat directly.
• After 3–5 days of starvation, ketone bodies supply more than half of cerebral fuel, cutting the daily glucose requirement to ~40 g and sparing muscle protein.

4. Adipose Tissue — the Triacylglycerol Bank

• Lipoprotein lipase (LPL) on the capillary endothelium hydrolyzes circulating chylomicron and VLDL triacylglycerol so fatty acids can enter the adipocyte; insulin induces LPL.
• Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) mobilize stored fat; both are activated by PKA-mediated phosphorylation downstream of glucagon and epinephrine and inhibited by insulin.
• Perilipin coats the lipid droplet and must be phosphorylated before lipases gain access — a favorite passage detail.

5. Erythrocyte — Glycolysis Only

No mitochondria means no TCA cycle, no $\beta$-oxidation and no oxidative phosphorylation. The red cell makes 2 net ATP per glucose and exports lactate; the pentose phosphate pathway supplies NADPH for glutathione reduction (see 4.4).

Hormonal Regulation of Fuel Metabolism

Fuel traffic is set by the insulin-to-glucagon ratio, modulated by the counter-regulatory hormones.

AAMC trap: insulin and glucagon act through opposing covalent modifications of the same enzymes. Phosphorylation activates glycogen phosphorylase and HSL but inactivates glycogen synthase and acetyl-CoA carboxylase. If a passage tells you PKA activity is elevated, you can predict the direction of all four at once.

The Adipostat: Leptin, Ghrelin and Long-Term Body-Mass Control

Body mass is defended around a set point by a negative-feedback loop running between adipose tissue and the arcuate nucleus of the hypothalamus.

• Leptin is secreted by adipocytes in proportion to total fat mass. In the arcuate nucleus it stimulates anorexigenic POMC/CART neurons and inhibits orexigenic NPY/AgRP neurons, reducing food intake and raising energy expenditure. Falling leptin during weight loss is the dominant signal, which is why leptin functions better as a starvation alarm than as a satiety signal.
• Ghrelin is released by gastric oxyntic cells during fasting, peaks immediately before meals, and activates NPY/AgRP neurons — the only well-characterized circulating orexigenic hormone.
• Adiponectin, unlike leptin, falls as adiposity rises; it activates AMPK, increasing fatty acid oxidation and insulin sensitivity.
• Short-term satiety signals include cholecystokinin, peptide YY and GLP-1 from the gut, plus vagal afferents reporting gastric distension.

  ADIPOSE MASS ↑ ──> Leptin ↑ ──> Arcuate nucleus
                                    ├── POMC/CART  (anorexigenic)  ↑ ──> intake ↓, expenditure ↑
                                    └── NPY/AgRP   (orexigenic)    ↓
  FASTING ──────> Ghrelin ↑ ──────> NPY/AgRP ↑ ──> intake ↑

Obesity and Metabolic Syndrome

Obesity is defined clinically by body mass index, $\text{BMI} = \text{mass (kg)} / [\text{height (m)}]^2$, with $25.0\text{--}29.9$ classified as overweight and $\ge 30.0$ as obese by the World Health Organization.

• Obese individuals have high, not low, circulating leptin: the defect is leptin resistance at the hypothalamus. Recombinant leptin therefore normalizes weight only in the rare congenital LEP loss-of-function patients (the human counterpart of the ob/ob mouse).
• Expanded visceral adipose releases free fatty acids and pro-inflammatory cytokines (TNF-$\alpha$, IL-6) that impair insulin receptor substrate signaling, producing insulin resistance.
• Resistance forces compensatory hyperinsulinemia; when $\beta$-cells fail, fasting hyperglycemia and type 2 diabetes mellitus appear. The cluster of central adiposity, dyslipidemia, hypertension and hyperglycemia is termed metabolic syndrome.