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Watanabe. Vessel Plus 2020;4:4 I http://dx.doi.org/10.20517/2574-1209.2019.27 Page 5 of 10

Suppressive effects of osmotin on the glucose uptake and differentiation of adipocytes
Visceral adipose tissue promotes insulin resistance and metabolic disorders, resulting in the development
of atherosclerosis. In particular, perivascular adipose tissue has been recently shown to have a close
linkage with atherosclerosis . Perivascular adipocytes residing in the vascular adventitia are recognized
[46]
[46]
as endocrine cells . Cross-talk between perivascular adipocytes and vascular cells in blood vessel wall
[47]
[48]
modulates the formation of atherosclerosis by releasing adipocytokines . Similar to adiponectin ,
osmotin suppresses the differentiation and proliferation of adipocytes by regulating the expression of p21,
p27, and cyclin-dependent kinase 2, as well as improves glucose uptake in 3T3-L1 adipocytes .
[33]
Protective effects of osmotin against ischemia-reperfusion injury in cardiomyocytes
A recent study has shown the protective effects of osmotin against myocardial ischemia-reperfusion
injury . Osmotin protects rat cardiac myoblast H9c2 cells against ischemia-reperfusion injury through
[11]
[11]
AdipoR1 by increasing phosphorylation of PI3K/Akt and decreasing that of NF-κB . Osmotin exhibits the
same cardioprotective effects of adiponectin and AdipoRon against ischemia-reperfusion injury [49,50] . These
findings indicate that osmotin as well as adiponectin and AdipoRon could prevent myocardial damage
following coronary events and ischemia-reperfusion injury.

In vivo anti-atherosclerotic effects of osmotin
Several studies have shown that adiponectin and AdipoRon suppress the development of atherosclerotic
-/-
lesions in apolipoprotein E-deficient (Apoe ) mice, an atherogenic mouse model, on a normal or high-fat
diet [51-53] . Recently, the anti-atherosclerotic effects of osmotin have also been investigated using a variety of
animal models in vivo. Treatment with osmotin suppresses abdominal fat accumulation in C57BL/6 mice
[33]
-/-
fed with a high-fat diet . In Apoe mice on a high-cholesterol diet, chronic infusion of osmotin prevents
the development of aortic atherosclerotic lesions accompanied by an improved vascular inflammation
[10]
and plaque instability . In this model, osmotin also improves fasting plasma glucose level, free fatty
[10]
acid level, and insulin resistance . Similarly, injection of osmotin lowers serum levels of total cholesterol
[31]
and triglyceride and prevents atherosclerosis in Wistar rats fed with a high-cholesterol diet . Osmotin
injection decreases serum levels of glucose, insulin, total cholesterol, and triglyceride in streptozotocin-
[32]
induced diabetic rats fed with a high-fat diet . In addition, it protects against obesity and diabetes-induced
nonalcoholic fatty liver disease in leptin-deficient obese (ob/ob) mice and leptin receptor-deficient diabetic
[54]
(db/db) mice . These effects are attributed to the stimulatory actions of osmotin on AMPK and PPAR-α
pathways. Therefore, osmotin is also expected to be useful in the preventive health care in diabetics in
[55]
future .

ANTI-INFLAMMATORY EFFECT
Atherosclerosis is an inflammatory vascular disease. The Canakinumab Anti-inflammatory Thrombosis
Outcome Study trial provided direct evidence that inflammation accelerates cardiovascular disease
in humans, by showing that a therapeutic antibody targeting IL1β decreased recurrent cardiovascular
[56]
events . This section introduces the beneficial effects of osmotin on inflammatory diseases other than
atherosclerosis. Osmotin suppresses LPS-induced neuroinflammation through AdipoR1 followed by toll-
[57]
like receptor 4 and NF-κB pathways in BV2 microglial cells . In addition, infusion of osmotin using
[58]
osmotic pumps attenuates dextran sodium sulfate-induced colitis in mice . These effects are consistent
with anti-inflammatory effects of adiponectin and AdipoRon [58-60] . The results from in vitro and in vivo
experiments indicate that osmotin as well as adiponectin and AdipoRon could prevent inflammatory
diseases.

NEUROPROTECTIVE EFFECT
Alzheimer’s disease is the most common form of dementia. The pathogenesis of Alzheimer’s disease
involves characteristics such as amyloid-β deposition, tau phosphorylation, and apoptotic neurode-