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Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90 Page 5 of 18
[45]
NAFLD is in intimate association with obesity and is characterized by features of adiposopathy .
However, adiposopathy may exist even with normal BMI, associating with an expansion of VAT, the so-
called metabolically obese normal weight (MONW) [46,47] . Adiposopathy may also occur in association with
a lipodystrophic phenotype, which can be genetic (rare genetic lipodystrophy disorders have an estimated
[48]
prevalence of one in a million ) or acquired [for example, an adverse effect of highly active antiretroviral
[39]
therapy in patients infected with human immunodeficiency virus (HIV) ].
Metabolically obese normal weight
BMI is an imperfect measurement of obesity/adiposity because it does not take into consideration
body composition (for example, differences in adipose and muscle mass), or the different patterns of
[49]
fat distribution . MONW refers to subjects with normal weight according to BMI, but with associated
cardiometabolic abnormalities such as IR, altered lipid profile, and/or hypertension . The estimated
[50]
[51]
prevalence of MONW is around 20% in normal weight subjects . The prevalence seems to gradually
increase from Caucasians to African American, Hispanics, and Asians . The prevalence of MONW
[50]
[50]
increases with age and with increasing BMI, even in the normal range . Importantly, MONW is
associated with a 3-fold increase in all-cause mortality, T2DM, and cardiovascular events, resembling obese
[48]
or overweight subjects with associated metabolic dysfunction . MONW might explain a high fraction
[39]
of patients with lean-NAFLD . The unsolved question is why normal weight patients develop metabolic
features of overweight/obese patients. There seems to be a “personal fat threshold” independent of BMI,
[52]
that when exceeded results in metabolic dysfunction . In fact, MONW subjects may have normal body fat
percentage, but different compartmentalization of fat, with central obesity, and particularly with increased
visceral fat. Indeed, epidemiological studies demonstrate a strong association between the MONW
[53]
phenotype and visceral adiposity .
[39]
VAT, that is intra-abdominal adipose tissue, accounts for 7%-15% of total body fat , and expands when
subcutaneous adipose tissue (SAT) surpasses its capability to adapt to a positive caloric balance . VAT is
[54]
morphologically and metabolically distinct from SAT. Adipocytes in VAT respond to energy surplus with
cell hypertrophy, with enlarged adipocytes presenting decreased ability to further store lipids, enhanced
[55]
lipolytic response, and blunted insulin-inhibition of lipoprotein lipase, demonstrating adipose tissue IR .
Unlike abdominal SAT, VAT is drained by the portal vein which allows exposure of the liver directly to
[54]
high concentrations of free fatty acids (FFA) and glycerol from oversized visceral adipocytes . In fact,
while in lean healthy subjects the VAT contributes to only 5-10% of the FFA that reach the portal vein, in
[56]
subjects with expanded VAT, its contribution can increase to 50% . FFAs that reach the liver contribute
to the accumulation of ectopic fat in the liver and promote hepatic IR . In the liver, FFAs activate nuclear
[57]
receptors such as peroxisome proliferator activated receptor (PPAR)-a and hepatic nuclear factor, which
profoundly modulate hepatic lipid metabolism, promoting the synthesis and export of triglycerides,
and explaining the strong association between hypertriglyceridemia and NAFLD, particularly in lean-
NAFLD .
[54]
[58]
The oversized VAT is prone to cell death and inflammation with macrophage infiltration , which are
responsible for local deregulation of adipokine secretion - with increased production of tumor necrosis
factor (TNF)-a and interleukin-6, and decreased production of the insulin-sensitizer and anti-inflammatory
[59]
adiponectin - and a systemic metabolic inflammatory state, further exacerbating IR .

Epidemiological studies showed that VAT was an independent risk factor for NAFLD, whereas BMI was
not [60-65] . Furthermore, there seems to be a dose-response association between VAT and prevalence of
[62]
[61]
NAFLD . In contrast, between SAT and NAFLD, a negative association was even described . Similarly,
longitudinal studies showed that VAT expansion was associated with incident NAFLD, whereas SAT
[66]
expansion was associated with NAFLD regression .