Differential effects of leptin on adiponectin expression with weight gain versus obesity

Abstract

Background/ObjectiveAdiponectin exerts beneficial effects by reducing inflammation, and improving lipid metabolism and insulin-sensitivity. Although adiponectin is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans.Methods/ResultsForty four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8-weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8 ± 1.2 kg resulted in increased adiponectin (p=0.03) while weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (p=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, while a leptin-antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in adipose tissue from normal-weight participants, but did not do so in adipose tissue from obese participants; and second, that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin.ConclusionsModest weight gain in healthy individuals is associated with increases in adiponectin, which correlate positively with changes in leptin. In-vitro, leptin induces adiponectin expression which is attenuated by increased caveolin-1 expression. Additionally, adipose tissue from obese subjects shows increased caveolin-1 expression, and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Circulating cytokines as determinants of weight loss-induced improvements in insulin sensitivity

“…However, some studies have reported no change in adiponectin levels despite improvements in glucoregulation [23–25]. Furthermore, in healthy weight subjects, adiponectin decreases with weight loss [26] and increases with weight gain [27], which is consistent with our findings.…”

Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice

“…While Ad and leptin were described as two independent factors which are dysregulated in MetS [48], recent studies found that leptin could induce Ad expression in differentiated human white preadipocytes [49], in ob/ob [50, 51] and in LDLR -/- mice [51]. Singh et al also suggested that leptin resistance may contribute to the reduced Ad expression in obese patients [49]. However, further in vivo and clinical investigations are necessary to confirm any causal relationship between leptin level and Ad expression.…”

Acute Overfeeding Does Not Alter Liver or Adipose Tissue-Derived Cytokines in Healthy Humans

“…HMW adiponectin is the major insulin-sensitizing isoform in humans [28] . Previous studies have shown that total adiponectin levels were increased after short term high-fat overfeeding for 3-7 days or 8 weeks [20,25,30] . No change in HMW adiponectin was observed in this study after 3 days.…”