Background:Non-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well.Identifying the biomarker of early diagnosis and early intervention approaches for non-alcoholic liver disease is unmet and required further investigation.Although the alpha-ketoglutarate(α-KG)is recently proposed to be a potential biomarker in differentiating patients with obesity from those with non-alcoholic liver disease,how α-ketoglutatate is involved in the fatty liver progression is not clear. Methods:A high-fat diet(HFD)feeding animal model,liver functional assays,and molecular approaches were adopted to clarify the impact of α-KG in fatty liver progression. Results:In the current study,it was found that dietary α-KG would inhibit weight gain in male and female mice fed with a normal chew or HFD.HFD feeding caused fatty liver in male mice,but α-KG treatment could substantially inhibit hepatic steatosis progression.Biochemical studies revealed the possible linkage of α-KG protective functions to lipid metabolism.Further analysis identified the important role of peroxisome proliferator-activated receptors in beneficial α-KG-mediated effects on fatty liver progression. Conclusions:The current study demonstrates the therapeutic potential of α-KG and how it may be used,via dietary supplementation,as a preventive intervention for non-alcoholic liver disease in obese patients.

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β ₃-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.