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ZKC discovered that in obese mice once a week systemic treatments (either subcutaneous or intravenous) with relatively small (40-100 μg/mouse) doses of ZKCPr1 specifically reduced visceral fat by 80-90%. Importantly, oral treatment of high fat diet fed obese mice with ZKCPr1 (0.5 mg/mouse) once every 5th day had similar effects (~75% reduction of visceral fat) with the exception that such delivery mode also reduced general obesity by ~30-40%. [Suitable coating should significantly reduce the effective dose of ZKPr1 and enhance its efficacy.]
Mechanism: ZKCPr1 binds to fat transporting chylomicrons and thus interferes with the binding of triglycerides to them eventually leading to less accumulation of fatty acids (formed by lipase mediated hydrolysis of triglycerides) to fat stores. At small doses, systemic ZKCPr1 preferentially inhibits fat accumulation in the visceral adipose tissue. Oral ZKCPr1 also reduces general obesity to some extent.
Applications:
(i) ZKCPr1 may be developed as a co-drug for obese humans treated with obesity drugs that reduce subcutaneous and excess visceral fat to similar extents (maximum 25%) i.e. without exerting large effects on the latter.
(ii) ZKCPr1 may also be developed as a stand-alone oral drug for normal weight subjects for specifically reducing excess visceral fat (belly fat). This would be particularly important for older adults who are limited in doing exercise.
When high fat diet fed obese mice were treated with small doses of ZKCPr1 delivered either orally or via an injection method, it substantially (up to 80%) reduced wasting of muscle proteins and muscle mass. Although not tested yet, it is very likely that ZKCPr1 will further reduce muscle wasting caused by weight loss drugs in obese mice and that these effects will be applicable to obese humans as well treated with such drugs.
ZKCPr1 also found to reduce muscle wasting in sarcopenic old mice by about 20-25%, associated with increased survival, which findings may be applicable to older obese and non-obese humans alike.
The effects of ZKCPr1 on the muscle are independent of its effects on visceral fat and may involve 3 separate mechanisms.
(i) ZKCPr1 is an anti-apoptosis protein helping survival of muscle cells under stress caused by, for example, obesity.
(ii) ZKCPr1 inactivates lipopolysaccharide (LPS), an important inducer of inflammation in obesity. In obese people the intestine becomes leaky and allows transport of LPS into the bloodstream that leads to increased muscle breakdown.
(iii) In vitro, ZKCPr1 inhibits myostatin, a negative regulator of muscle cell viability. Such an effect of ZKCPr1 may well occur in vivo as well.
ZKC used a special method to determine that high serum triglycerides directly related to excess visceral fat. Administration of small doses of ZKCPr1 by either administration method to obese mice practically normalized serum triglyceride levels. Since studies have consistently linked high triglyceride levels to heart disease, heart attacks, and stroke, especially in people with low levels of HDL cholesterol and those with type 2 diabetes, confirmation of the above effects of ZKCPr1 on this lipid in humans would be a significant addition to the clinical practice.
Treatment of obese mice with small doses of ZKCPr1 by any of the administration methods reduced high level of blood glucose from 8.5-10 mM down to 6.5-7 mM. If this results will hold in obese diabetic humans, then along with the reduction of visceral fat, ZKCPr1 would be expected to make diabetic drugs more effective.
In response to the above challenge, ZKC has synthesized many heterocyclic compounds and tested some of them for their effects on weight loss maintenance. Subcutaneous daily treatment of obese mice continuously kept on high fat diet with a low dose of two of these compounds (separate treatments) for two weeks resulted in minimal weight gain during a subsequent treatment-free 5 weeks period. The data indicates that the compounds suppress appetite. The company thinks that treatment with this kind of drug, if it works in humans as well, would be a great help for those who need more time to decide if they want to go back to using a weight loss drug.