| Adipose tissue is distributed throughout the human body and is the main storage site for excess energy derived from our food intake. As a highly active endocrine organ, adipose tissue secretes many kinds of adipokines exerting effects on either local adipose tissue or other main organ in the body. Homeostasis of these adipokines is closely related to metabolism, cardiocerebrovascular function, immunity and inflammation. Disruption of the homeostatic state of adipokines can lead to abnormality in metabolism and immunity contributing to the pathogenesis of obesity, atherosclerosis and cardiovascular disease. Therefore, it is important to have a better understanding of known adipokines as well as to identify new ones. Our work has demonstrated the pivotal roles of Metrnl and Nampt in metabolism. We have also illustrated the regulation mechanisms of these adipokines.In the first part, we have clarified the functional role of adipocyte Metrnl in regulating insulin sensitivity. We have previously reported that Metrnl is a novel secretory protein with high level of expression in subcutaneous fat in mice and human. Metrnl was found to be downregulated in white adipose tissue(WAT) under calorie restriction, while remained at a high level in WAT in diet-induced obese mice. Metrnl can be significantly elevated during adipocyte differentiation, indicating its functional role in white adipose biology and metabolic homeostasis. We thus generated adipocyte-specific Metrnl overexpression mice(Metrnl Tg) and adipocyte-specific Metrnl knockout mice(Metrnl-/-) to further study Metrnl function in vivo. In this study, we optimized and established a standard operation procedure for Metrnl-/- mice genotyping. Using glucose tolerance test(GTT), we have shown adipose-specific deletion of Metrnl greatly aggravated insulin resistance induced by high fat diet(HFD), whereas overexpression of Metrnl antagonized insulin resistance caused by HFD or leptin deletion. In addition, Metrnl greatly increased insulin stimulated AKT phosphorylation in WAT. We further explored the underlying mechanism of the insulin sensitization effect of Metrnl and found all the effects are results of Metrnl-mediated inhibition of inflammatory factors, improvement of lipid metabolism and enhancement of adipocyte differentiation. We have also detected Metrnl secretion in both adipose tissue and mature adipocyte, and demonstrated its promotion effect on adipocyte differentiation in a secreted manner. Inhibition of PPARγ by either small molecular inhibitor or lentivirus vector abolished insulin sensitization effect of Metrnl, indicating PPARγ as an indispensable molecule in Metrnl regulated insulin sensitivity. In this part, we have demonstrated an important role of Metrnl in white adipose biology that adipocyte Metrnl antagonizes obesity-induced insulin resistance by promoting adipocyte differentiation, improving metabolic homeostasis and inhibition of inflammation mediated by PPARγ pathway. Metrnl will be a promising therapeutic target for metabolic syndrome and type 2 diabetes.In the second part we illustrated an important role of Nampt in calorie restriction-mediated beneficial effects in oxidative stress and mitochondrial biogenesis. Calorie restriction(CR), also known as dietary restriction, is a dietary intervention that restricts calorie intake. It is considered to be beneficial in extending life span and plays important roles in regulating metabolic homeostasis and diseases. SIRT family is a key regulator mediating CR effect and its activity is largely dependent on nicotinamide mononucleotide(NAD+) biosynthesis. Nicotinamidephosphoribosyltransferase(Nampt) is the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, and we have previously reported its functional roles in CR-induced metabolic improvement. Here, we demonstrated inhibition of Nampt using a specific chemical inhibitor FK866 could abrogated CR-induced enhancement of SIRT3 activity, reduction of oxidative stress, improvements of antioxidative activity and mitochondrial biogenesis, thus clarifying a beneficial role of Nampt in oxidative stress and mitochondrial biogenesis. |
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