Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 （IL-15） is used as a new example to explain the beneficial effects of the pro- inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-KB. IL-15 binds to its receptor that contains three different subunits （~, [5 and 1,） to activate JAK/STAT, PI3K/Akt, IKK/NF-KB and JNK/API pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

Mitochondrial inhibitor as a new class of insulin sensitizer

Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

Mechanisms of insulin resistance in obesity

Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance.In those hypotheses,inflammation,mitochondrial dysfunction,hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention.Oxidative stress,endoplasmic reticulum(ER)stress,genetic background,aging,fatty liver,hypoxia and lipodystrophy are active subjects in the study of these concepts.However,none of those concepts or views has led to an effective therapy for type 2 diabetes.The reason is that there has been no consensus for a unifying mechanism of insulin resistance.In this review article,literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance,in which insulin resistance is a result of energy surplus in cells.The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase(AMPK)signaling pathway.Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance.In support,many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.The effective therapies such as weight loss,exercise,and caloric restriction all reduce ATP in insulin sensitive cells.This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity,which may apply to insulin resistance in aging and lipodystrophy.

NF-κB/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis

The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.