**Core Concept**
The major site of action of Antidiuretic Hormone (ADH), also known as Vasopressin, involves its interaction with specific receptors in the kidney, leading to increased water reabsorption and decreased urine production.

**Why the Correct Answer is Right**
ADH acts on the V2 receptors in the collecting ducts of the nephrons in the kidneys. When ADH binds to these receptors, it triggers a signaling cascade that increases the expression of aquaporin-2 water channels in the apical membrane of the collecting duct cells. This results in increased water reabsorption, concentrating the urine and conserving water in the body.

**Why Each Wrong Option is Incorrect**
* **Option A:** This option is incorrect because ADH does not primarily act on the V1 receptors in the blood vessels to cause vasoconstriction. While V1 receptors are indeed activated by ADH, this is not its major site of action.
* **Option B:** This option is incorrect because ADH does not act on the liver to regulate glucose metabolism or lipid synthesis. ADH's primary function is to regulate water balance, not glucose or lipid metabolism.
* **Option C:** This option is incorrect because ADH does not act on the hypothalamus to regulate body temperature or appetite. While ADH is produced in the hypothalamus, its site of action is in the kidneys, not in the hypothalamus itself.

**Clinical Pearl / High-Yield Fact**
ADH deficiency, also known as diabetes insipidus, can lead to excessive thirst and polyuria due to the inability to concentrate urine. This can be caused by a variety of factors, including genetic mutations, head trauma, or certain medications.

**Correct Answer:** D.