The Role of Leptin in NAFLD

Nonalcoholic fatty liver disease (NAFLD) is common not only in Western countries where obesity prevalence is rising, but it is also being increasingly recognized in individuals with normal body mass index (BMI). There is little controversy about our incomplete knowledge of the pathogenesis of fatty liver. As the pieces slowly come together, it would be imprudent to rush to judgment about the relative importance or role of any single molecule. Case in point: leptin. Leptin, an adipocytokine produced primarily in visceral adipocytes, is the gene product of the ob gene, identified in the mid 1990s. Leptin receptors are found primarily in the hypothalamus but also in vascular endothelial cells. Leptin’s effects on the hypothalamus regulate hunger and energy expenditure. In humans, leptin levels correlate with percentage body fat and are correspondingly higher in women. In the genetically obese mouse model (ob/ob), a mutated gene results in little or no leptin production. These obese mice lose weight with leptin replacement, and hence, in that model, leptin is clearly involved in obesity. The story in humans is different and what role leptin may play remains unclear. Unlike the animal models of obesity, obese humans have elevated leptin levels, indicating resistance to leptin rather than a deficiency. This is an important difference to be kept in mind when considering leptin and its receptor in the pathogenesis of NAFLD. There is a large body of evidence implicating leptin in the scheme of NAFLD overall. It is generally accepted that insulin resistance is almost always present in NAFLD, particularly in nonalcoholic steatohepatitis (NASH). Serum leptin in multivariate analysis is related to insulin levels, fat mass, lean mass, and correlates strongly with insulin resistance in humans. In 47 biopsy proven cases of NASH, leptin levels were twice those found in controls matched for BMI, gender, and age. While there was no direct correlation with degree of inflammation or fibrosis, the authors concluded that leptin is likely involved in the pathogenesis of insulin resistance, and hence steatosis. There may be hormonal interactions resulting in differences between genders as leptin levels differ in men and women, even after adjusting BMI. In young Japanese adults with ultrasound confirmed steatosis and mean BMI of less than 25, higher leptin levels were found in women, with a strong correlation to visceral/subcutaneous fat ratio. Gender differences also appear to influence the circulating soluble form of the leptin receptor, which determines the free serum leptin index. In a study of 118 healthy young adults, the leptin receptor levels appeared to be regulated by gender, adiposity, and hormone levels. These studies raise further questions about the role of sex hormones, degree and location of adiposity, and the role of circulating soluble leptin receptor in addition to leptin itself. Visceral adiposity appears to be the metabolically active store of fat cells, often quantified by waist-to-hip ratio measurements. Not all published studies have shown these aforementioned relationships. Chalasani et al compared 26 biopsy-proven NASH patients to 20 nonbiopsied controls and found no difference in leptin levels between the two groups. However, no relationship between leptin and insulin resistance was found either, making it difficult to understand if this were truly a representative group. The correlation of leptin to subcutaneous fat in that study was also unexpected, since most other studies point to visceral fat as the metabolically