De novo lipogenesis in adipose tissue of lean and obese women: application of deuterated water and isotope ratio mass spectrometry.

OBJECTIVE: To evaluate the feasibility of using deuterated water and isotope ratio mass spectrometry to measure de novo fatty acid synthesis in adipose tissue, and to compare this parameter in obese and lean women. SUBJECTS: Six lean and six obese premenopausal Caucasian women in the main study and three obese Pima Indians in a pilot study. MEASUREMENTS: Deuterated water was administered orally twice daily for 14 days to create stable deuterium enrichment in body water, during which series of blood samples were collected to measure body water deuterium enrichment and deuterium incorporation into plasma total Triacylglycerol (TG) fatty acids and total cholesterol. Subcutaneous fat at different sites were sampled at the beginning and the end of deuterium administration to measure deuterium incorporation into TG fatty acids. RESULTS: Fractional de novo synthesis rate of TG fatty acids in adipose tissue was 0. 014+/-0.005 and 0.014+/-0.007% in lean and obese Caucasian women, corresponding to 2+/-0.7 and 5.6+/-3.2 g (P=0.3) of fatty acids synthesized daily, respectively. Plasma TG fatty acids and cholesterol synthesis rates were comparable to those reported previously. A pilot study showed that de novo lipid synthesis in adipose tissue of obese Pima Indians was also quantitatively minor. CONCLUSION: Human adipose tissue, like the liver, does not make a major contribution to whole body lipogenesis under eucaloric conditions. A combination of deuterated water and isotope ratio mass spectrometry is a useful research tool for studying accumulation of de novo synthesized lipids in human adipose tissue.

Entrainment of the diurnal rhythm of plasma leptin to meal timing.

To identify the physiologic factor(s) that entrain the diurnal rhythm of plasma leptin, leptin levels were measured hourly after changes in light/dark cycle, sleep/wake cycle, and meal timing. Four young male subjects were studied during each of two protocols, those being a simulated 12-h time zone shift and a 6.5-h meal shift. During the baseline day, plasma leptin demonstrated a strong diurnal rhythm with an amplitude of 21%, zenith at 2400 h, and nadir between 0900 and 1200 h. Acute sleep deprivation did not alter plasma leptin, but day/night reversal (time zone shift) caused a 12+/-2 h shift (P < 0.01) in the timing of the zenith and nadir. When meals were shifted 6.5 h without changing the light or sleep cycles, the plasma leptin rhythm was shifted by 5-7 h (P < 0.01). The phase change occurred rapidly when compared with changes in the diurnal rhythm of cortisol, suggesting that leptin levels are not acutely entrained to the circadian clock. The leptin rhythm was altered by meal timing in a manner very similar to the rhythm of de novo cholesterol synthesis. We conclude that the diurnal rhythm of plasma leptin in young males is entrained to meal timing.

Effect of meal timing on diurnal rhythm of human cholesterol synthesis.

To test whether the diurnal rhythm of cholesterol synthesis in humans is entrained to meal timing, the effect of a 6.5-h delay of mealtimes was investigated in four normal lipidemic male subjects. Cholesterol fractional synthetic rate was measured by deuterium incorporation from body water using blood sampling every 2 h. The baseline was a 24-h control period in which three Western-style meals were consumed at 0700, 1150, and 1640, followed by 3 days in which meals were delayed by 6.5 h, i.e., meals consumed at 1330, 1820, and 2310 without changing the sleep-wake and light-dark cycles. Cholesterol synthesis was maximal at 2200 +/- 0200 and minimal at 1130 +/- 0050 on the baseline day. On day 1 of the shifted meals, the maximum was delayed 6.0 +/- 0.5 h and the nadir was not changed. On day 3, the maximum was delayed 8.6 +/- 3.7 h and the minimum was delayed 6.5 +/- 2.4 h from baseline. The mean amplitude of the cholesterol rhythm was significantly greater on day 3,233 +/- 35%, compared with baseline which was 109 +/- 15%. A strong negative correlation (r = -0.66 +/- 0.10) was found between the rhythms of cholesterol synthesis and cortisol during the baseline day, but there was a phase delay in the rhythm of cholesterol synthesis relative to cortisol on day 1 and day 3. Findings indicate that the 24-h variation in cholesterol synthesis is strongly dependent on meal timing.

Diurnal rhythmicity of human cholesterol synthesis: normal pattern and adaptation to simulated "jet lag".

The diurnal rhythm of cholesterol synthesis was determined by deuterium incorporation from body water in five normolipemic men studied during a 24-h baseline period and on the 1st, 2nd, and 4th days of a simulated 12-h time zone shift achieved by delaying sleep times and, starting on the 2nd day, meal-times. Profiles of plasma cortisol and thyrotropin (TSH) were obtained simultaneously. Under baseline conditions, cholesterol synthetic rates varied from essentially zero in the morning to maximal values around midnight. On the 1st shifted day, this diurnal variation was unaltered despite sleep-wake reversal. The diurnal pattern of cholesterol synthesis, however, was shifted 5 h on the 2nd shifted day and approximately 12 h on the 4th. The diurnal variation of synthetic rate cholesterol fractional synthesis and plasma cortisol levels was negatively correlated on both the baseline day and the 1st shifted day. A positive correlation with the TSH rhythm was found on the 1st day only. During the 2nd and 4th days, the rhythm of cholesterol synthesis adapted faster than the rhythms of cortisol and TSH. These findings indicate that cholesterol synthesis is not acutely entrained by the sleep-wake cycle nor is it primarily entrained by the circadian clock.