Serum leptin as a mediator of the influence of insulin resistance on hepatic steatosis in youths with excess adiposity

Highlights

• Nonalcoholic fatty liver disease (NAFLD), is the most common early driver of chronic liver disease in the Western world.

• We identified that insulin resistance is positively correlated with NAFLD and this relationship is mediated by leptin.

• In adolescents with suspected or at risk of NAFLD should be screened for insulin resistance and serum leptin levels.

• Longitudinal studies are required to elucidate the mechanism underlying the link between insulin resistance, serum leptin, and NAFDL.

Abstract

Background and aims

The relationship between insulin resistance (IR) and hepatic steatosis (fatty liver) is well known; however, the extent to which the satiety hormone leptin acts as a confounder or mediator in this relationship is uncertain. We examined whether the association between IR and hepatic steatosis is mediated by leptin in Colombian adolescents with excess adiposity.

Methods and results

A total of 122 adolescents (mean age: 13.4 years; 68% girls) participated in the study. We assessed body composition, hepatic steatosis (as defined by the controlled attenuation parameter [CAP]), cardiometabolic risk factors (body mass index, waist circumference, body composition), biochemical variables (leptin, insulin, glucose, lipid profile, cardiometabolic Z-score, transaminases, etc.), and physical fitness (cardiorespiratory fitness and grip strength). Partial correlation, regression, and mediation analyses were conducted using the Barron and Kenny framework.

Results

Ninety-two youths (75.4%) had IR. Mediation analysis revealed a positive relationship between Homeostasis Model Assessment-IR (HOMA-IR) and CAP (β_dir = 3.414, 95% confidence interval [CI]: 1.012 to 5.816, p < 0.001), which was attenuated when leptin was included in the model, thus indicating that leptin mediates this relationship (β_ind = 1.074, 95% CI: 0.349 to 2.686, p < 0.001). The percentage of the total effect mediated by leptin was 21%. Regarding sex, the mediation effect of leptin remains significant among boys (β_ind = 0.962, 95% CI: 0.009 to 2.615, p < 0.001), but not in girls (β_ind = 0.991, 95% CI: 1.263 to 5.483, p = 0.477).

Conclusions

The findings are clinically relevant to consider leptin levels as a surrogate marker of insulin sensitivity when assessing youths with excess adiposity and/or suspected Nonalcoholic hepatic steatosis or nonalcoholic fatty liver disease (NAFLD).

Introduction

Nonalcoholic hepatic steatosis or nonalcoholic fatty liver disease (NAFLD) is the most common early driver of chronic liver disease in the Western world [1]. The overall prevalence of NAFLD varies between ethnic and racial groups, with Latin Americans presenting disproportionately higher rates [2]. The prevalence of NAFLD in obese pediatric populations is reported to range from 7.6% to 34.2% [3], and 23% of affected individuals have type 2 diabetes [4]. Besides being a risk factor for metabolic syndrome (MetSyn), insulin resistance (IR) is also recognized as an independent risk factor for developing NAFLD by favoring the onset of dyslipidemia [5]. The relationship between IR and MetSyn is multifaceted and includes parameters such as central obesity, glucose intolerance, hypertension, and dyslipidemia, while the clustering of elevated levels of these comorbidities progress from childhood to adolescence and adulthood [6].

We do not fully understand the mechanisms linking IR to NAFLD, although it is believed that some adipokines are involved in liver steatosis and metabolic crosstalk [7]. Leptin, a 16-kDa plasma protein, was the first adipokine to be isolated and identified. Leptin appears to play a key role in regulating the body's energy expenditure and, more specifically, in controlling food intake and sympathetic nervous system activity [8]. There is increasing evidence that leptin is involved in metabolic disorders, with elevated leptin levels observed in obesity, MetSyn, type 2 diabetes, and NAFLD [9]. Similarly, almost 10% of the obese population presents abnormal leptin plasma levels and in some cases obesity has even been attributed to impaired leptin production in adipose tissue [10]. However, subjects with NAFLD show higher levels of circulating plasma leptin due to a state of leptin resistance associated with hepatic lipid [11].

Paradoxically, animal studies have shown that leptin deficiency may lead to hepatic steatosis (e.g., in leptin-deficient ob/ob mice), which can be reversed by leptin replacement [12]. In this context, Leclercq et al. [13] have reported that leptin administration regulates lipid and glucose homeostasis in the liver based on rodent models of dysfunctional leptin signaling (ob/ob). There is evidence of an association between IR and NAFLD. When analyzing the temporal relationship in terms of the onset of hepatic steatosis compared to insulin and leptin resistance in rodent models, Zhang et al. [14] demonstrated that insulin resistance developed first, followed by leptin resistance, and subsequently steatosis 2–3 weeks later. However, the association between leptin and hepatic steatosis has led to contradictory conclusions even though leptin resistance, a condition commonly observed in obese subjects, seems to be a major driver of hepatic lipid accumulation and, hence, steatosis [12]. Interestingly, Cortés et al. [15], showed that leptin might ameliorate IR and hepatic steatosis in mouse models, while Petersen et al. [16] reported that leptin reverses IR and hepatic steatosis in patients with lipodystrophy. Thus, most the existing studies have been conducted in rodent models or obese adults, but there are no data available among youths.

To date, the potential role of leptin in attenuating or modifying the relationship between IR and hepatic steatosis remains unknown and, to the best of our knowledge, has not been examined in younger subjects. Considering the increasing number of obese adolescents occurring in parallel with a greater prevalence of hepatic steatosis, the present study was conceived with two main aims: 1) to analyze the relationship between IR and hepatic steatosis in youths with excess adiposity; and 2) to determine whether this relationship is mediated by leptin.