Pusalavidyasagar, Snigdha

Background: Normal weight adults gain leg fat gain via adipocyte hyperplasia and upper body subcutaneous (UBSQ) fat gain via adipocyte hypertrophy. Objective: To understand whether regional fat loss mirrors fat gain and whether leg fat loss results in decreased adipocyte number vs. size. Design: We assessed UBSQ, leg and visceral fat gain and loss in response to over- and underfeeding in 23 young, healthy normal weight adults (15 men). Participants gained ∼5% weight over 8 weeks and lost ∼80% of gained fat over the following 8 weeks. We measured abdominal subcutaneous and femoral adipocyte size and number after weight gain and loss. Results: Volunteers gained 3.1 ± 2.1 kg of body fat with overfeeding and lost 2.4 ± 1.7 kg with calorie restriction. Although upper body subcutaneous (UBSQ) fat and visceral fat gains were completely reversed with weight loss, leg fat had not yet returned to baseline values by 8 weeks. Abdominal and femoral adipocyte size decreased significantly with weight loss, but the number of adipocytes did not decrease. Abdominal adipocyte size decreases correlated (rho= 0.76, p = 0.001) with UBSQ fat mass decreases and femoral adipocyte size decreases correlated (rho= 0.49, p=0.05) with leg fat mass decreases. Conclusion: UBSQ and visceral fat depots increase and decrease proportionately with short term weight gain and loss, whereas gain and loss of leg fat are less well linked. Loss of lower body fat is due to reduced fat cell size, not number, which may result in long-term increases in leg fat cell number. This may have implications for long-term weight control.

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1–dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P =0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.