The Effects of Acute Weight Gain and Acute Calorie Deprivation on Marrow Adipose Tissue

Marrow adipocytes have been identified as a component of the bone marrow micro-environment.
Evidence exists suggesting that marrow fat plays an important physiologic role in both bone
mineral and energy metabolism in humans. Studies have shown that nutritional status,
particularly body fat distribution, may be important in marrow fat. For example, anorexia
nervosa, a state of low body fat, is associated with elevated marrow adiposity and low bone
mineral density. However, it is not known whether this is in direct response to nutritional
deprivation or other hormonal changes that occur in anorexia nervosa. Drugs known to cause
adipose redistribution and associated with low bone mass, such as the thiazolidinediones and
glucocorticoids, have also been shown to stimulate the accumulation of marrow adipocytes.
Therefore, the relationship between bone marrow fat, bone mass, body fat depots and their
hormone regulators is a dynamic one and not yet well understood. Although studies have shown
an inverse relationship between high marrow adiposity and low bone mineral density (BMD), the
physiologic role of marrow adipose tissue has not been defined nor its relationship to
hormonal factors in humans. A role for marrow adipose tissue (MAT) in mineral and energy
metabolism is further supported by the fact that a number of pathologic states are associated
with increased marrow adiposity. Visceral adipose tissue, intramyocellular lipids (IMCL),
intrahepatic lipids (IHL) and serum triglycerides, all of which are elevated in obesity, are
also positive predictors of MAT, but whether acute weight gain in humans results in elevated
marrow adiposity is unknown. Therefore observing changes in marrow fat during acute weight
gain and acute nutritional deprivation will further the understanding of the role of marrow
adiposity in energy homeostasis. While it is known that markers of bone formation
dramatically decrease after only 4 days of fasting, it is not known how quickly marrow fat
can change in response to physiologic cues. In a rat model, increases in marrow fat were
observed after 14 days in space suggesting that changes in marrow adiposity may occur acutely
in the human model as well.

Inclusion Criteria:

1. Men and women, ages 21-45 years

2. 101-120% of ideal body weight as defined by the 1983 Metropolitan Life Insurance
Height and Weight Tables

3. Normal thyroid function

4. Regular menses (women) - Female subjects will start the study within 1 week of Day 1
of their menstrual period

5. Normal transaminase levels (AST/ALT)

Exclusion Criteria:

1. Any disease known to affect bone metabolism, including untreated thyroid dysfunction,
Cushing's syndrome, or renal failure

2. Any medication known to affect bone metabolism -- including systemic steroids or
immunosuppressants -- within three months of the study, excluding estrogen and
progestins. Patients receiving depot medroxyprogesterone (Depo-Provera) will be
excluded from participating for six months after their last injections.
Bisphosphonates must have been discontinued for at least one year before participation

3. Serum potassium <3.0 meq/L

4. History of eating disorder

5. Pregnant and/or breastfeeding (women)

6. Diabetes mellitus

7. Active substance abuse, including alcohol

8. Contraindications to MRI: cardiac pacemaker, metal implants, claustrophobia

9. History of chemotherapy or radiation therapy

10. History of a bleeding disorder or use of anti-platelet medications

11. Allergy to allopurinol

12. The study physician feels that the subject may not be able to safely complete the
study or may place themselves at risk by undergoing the study