Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain.
A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells.
Analyses of metabolic parameters in maternal venous and umbilical venous plasma revealed significantly increased insulin and leptin as well as slightly increased glucose and TNF-α values in the obese and obese-GDM groups.
Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency.
Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery.
Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity.
Furthermore, hormones that affect energy homeostasis also affect sleep/wake states: the orexigenic hormone ghrelin promotes wakefulness, and the anorexigenic hormones leptin and insulin increase the duration of slow-wave sleep.
If leptin and insulin sensitivities increase concurrently, the combined effect could be a decrease in fat mass, consistent with the fact that increasing insulin sensitivity is often associated with fat mass loss in trials.
Impaired appetite regulation, in terms of elevated insulin levels and decreased leptin levels, occurs in early psychosis, before antipsychotic treatment.
In first-degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of metabolic syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk.
Liver-specific AlbCre+Cc1<sup>fl/fl</sup> mutants exhibited impaired insulin clearance and hyperinsulinemia at 2 months, followed by hepatic insulin resistance (assessed by hyperinsulinemic-euglycemic clamp analysis) and steatohepatitis at ~ 7 months of age, at which point visceral obesity and hyperphagia developed, in parallel to hyperleptinemia and blunted hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection of leptin.
Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia.
Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression.
Serum leptin levels were unchanged by hyperinsulinemia for 3 h during the clamp prior to the fast, while hyperinsulinemia for 3 h after 6 days of fasting increased serum leptin by 25% (P < 0.01).
Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels.