113 This can lead to diet-induced steatosis, dyslipidemia, and both

insulin and leptin resistance.114 Rimonabant, the prototypic CB1R antagonist, reduced hepatic steatosis and improved dyslipidemia in fa/fa diabetic Barasertib clinical trial rats, disproportional to effects on food intake.116 This preliminary observation led to the suggestion that pharmacological approaches to metabolic regulation could have beneficial effects in NAFLD/NASH.116,117 Unfortunately, clinical development of Rimonabant as an anti-obesity agent was discontinued because of a high frequency of depression. Other systems involved in both CNS and peripheral metabolic regulation include NPY and melanocortin.118,119 Thus, stress in rodents releases NPY

from sympathetic nerves. In turn, this up-regulates NPY and its Y2 receptor in abdominal fat by a glucocorticoid-dependent mechanism, resulting in abdominal obesity.118 There is also evidence that blockade of CNS melanocortin receptors (MCR) triggers mobilization of lipid uptake, triglyceride synthesis and fat accumulation in WAT, changes that are independent of food intake.119 This indicates that loss-of-function mutations in MC4R, which have been associated with human obesity, may affect both CNS and peripheral metabolic regulation in HIF inhibitor review favor of adiposity. One reason for earlier controversies about NAFLD and NASH is that not all affected patients are obese, although we contend that most are either over-weight or ‘metabolically obese, normal weight’.120 From a burgeoning literature [reviewed in 7,121], the most consistent relationships with NASH have been between central obesity, reflecting visceral adiposity, and insulin resistance. Anthropometric indicators of visceral (central) obesity (VAT), such as waist circumference, have been bolstered by determination of hepatic triglyceride medchemexpress stores using MRS.70,122 Among morbidly obese individuals, steatosis correlates directly with VAT,122 while correlations with subcutaneous adipose tissue (SAT)

stores are less clear, with inconsistent results between studies (some positive, others no correlation).123–126 The relationship between central obesity and NAFLD/NASH is consistent with the proposal that metabolically unhealthy fat is what leads to insulin resistance and cardiovascular disease,127–129 as supported by the strong relationship between central obesity and cardiovascular death and even all-cause mortality.130,131 In non-obese subjects, the relationship between waist circumference and NAFLD/NASH is less clear. Musso and colleagues compared non-obese, non-diabetic NASH patients to controls; there was no difference in waist circumference or waist-hip ratio.