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Page 6 of 18 Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90

Studies on lean-NAFLD showed similar associations between hepatic steatosis and both central obesity and
visceral fat [20,29,67-69] . Interestingly, lean-NAFLD patients present lower levels of adiponectin than their lean
healthy counterparts. Furthermore, even though lean-NAFLD patients tend to have lower levels of leptin
compared to overweight/obese NAFLD patients, which translates to lower body fat, they have similar levels
of adiponectin, suggesting similar adipose tissue malfunction and adiposopathy [28,68,70] .

The differentiation between upper and lower body fat has unraveled interesting new concepts on the
[71]
metabolic consequences of body fat distribution . SAT can be divided into upper body fat, which refers to
abdominal subcutaneous fat, and lower body fat, which refers to gluteofemoral subcutaneous fat. Data from
the Third NHANES, in the US, showed that normal weight subjects with upper body obesity (defined by
an increased WTH ratio) had the highest all-cause mortality rate, more than doubling both normal weight
and overweight/obese subjects without upper body obesity, and being matched only by overweight/obese
[72]
that also had upper body obesity . Unlike abdominal/upper body fat, femoral/lower body subcutaneous
fat seems to be an independent protective factor for cardiometabolic diseases and mortality [71,73,74] . In
fact, abdominal SC fat depots are physiologically different from femoral SC fat depots. Abdominal SAT
demonstrates a rapid diet-derived fat uptake and high lipid turnover responsive to adrenergic activation.
Femoral SAT, on the contrary, has a low lipid turnover and is more efficient in storing fat, mounting a
hyperplasic response (recruiting new adipocytes from precursors rather than enlarging the adipocytes as
[71]
[75]
occurs in abdominal SAT) to a caloric challenge , and being less susceptible to inflammation . Upper
and lower body fat are under different epigenetic control of genes involved in adipocyte differentiation,
with higher expression of TBX5 and HOXA5 in upper SAT and higher expression of HOTAIR in lower
[76]
SAT . Noteworthy, polymorphisms in genes that regulate adipocyte differentiation such as CCDC92,
DNAH10, and L3MBTL3, associate with lower body fat, and paradoxically with IR, T2DM, and coronary
heart disease. This suggests that subjects with predisposed limited storage capacity of peripheral adipose
[77]
tissue, are more susceptible to IR and to cardiometabolic diseases .
Concordant with a role of decreased lower body fat in the susceptibility to NAFLD in lean individuals, WC
and WTH ratio are better predictors for incident lean-NAFLD as compared to BMI [34,78] .

Sarcopenia
[79]
Sarcopenia, that is, loss of skeletal muscle mass and function, seems to confer susceptibility to NAFLD .
Sarcopenia may help explain the occurrence of hepatic steatosis in patients with BMI within the normal
range, since BMI cannot differentiate between fat deprived nor muscle mass deprived subjects.

Data from the Korean National Health and Nutrition Examination Survey (KNHANES) showed that
sarcopenia associates with NAFLD and liver fibrosis, independent of obesity and IR . Other studies and
[79]
recent meta-analysis corroborated that data [80-85] . Furthermore, skeletal muscle mass seems to be lower in
lean versus obese patients with NAFLD .
[86]
The relationship between sarcopenia and metabolic dysfunction goes both ways. IR and chronic
[87]
inflammation promotes myosteatosis , which exacerbates muscle catabolism. On the other hand,
sarcopenia (and disturbed myokines secretion) promotes IR and hepatic steatosis .
[88]
IR and T2DM promote muscle depletion and dysfunction through several mechanisms: (1) FFAs released
by an insulin resistant adipose tissue inhibit the growth hormone/insulin growth factor-1 axis, decreasing
[89]
its protective effect on muscle regeneration ; (2) myosteatosis associates with a blunted activation of
muscle peroxisome proliferator-activated receptor gamma coactivator-1a and an increase in oxidative
stress resulting in mitochondrial dysfunction ; and (3) an increase in gluconeogenesis drives proteolysis.
[90]
Obesity and NAFLD associate with a small grade inflammatory state, with an increase in proinflammatory