Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children

Abstract

Background: Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight. Objective: To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO). Design: This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO). Results: A total of 69 children (HOZ28, CHZ18, SOZ23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (P!0.05). Conclusion: No differences in fasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children

“…This increased insulin response probably directs the ingested energy substrate to be stored as fat leading to obesity which was supported by the previous studies [5,15]. Shaikh et al also demonstrated that fasting insulin levels were similar in hypothalamic obese children and exogenously obese children [27].…”

“…Shaikh et al hypothesized that hyperinsulinism is a result of, instead of a reason for, hypothalamic obesity [27]. Srinivasan et al demonstrated that patients with hypothalamic obesity have no increased insulin resistance even if they have signs of metabolic syndrome [28].…”

“…Leptin and insulin-based theories are among the most encouraging ones. Resistin, which is a cytokine produced by adipose tissue, monocytes, and macrophages, has also been suggested to be involved in insulin resistance and obesity [17], which has not been previously evaluated in hypothalamic obesity except one very recent study by Shaikh et al [27].…”

Food intake regulating hormones in adult craniopharyngioma patients

“…Increased leptin levels in CP patients have been reported before (11,30). Two causes could account for this: on the one hand, the higher FM of CP patients and on the other hand, a leptin resistance caused by the damage of the hypothalamus (31).…”

Hypothalamic Obesity: Prologue and Promise

“…Importantly, the satiating effect of gut peptides, such as cholecystokinin and glucagon-like peptide-1 (GLP-1), is titrated to the overall state of energy balance through hypothalamic actions of circulating leptin and insulin [51]. As HO subjects have intact hindbrain weight homeostatic structures [52], their high circulating leptin [53, 54] can bind to hindbrain receptors, theoretically leading to an amplification of GLP-1 effects on energy intake and homeostasis.…”