OBJECTIVEWe examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet.RESEARCH DESIGN AND METHODSIn dietary-obese C57BL/6J mice, sodium butyrate was administrated through diet supplementation at 5% wt/wt in the high-fat diet. Insulin sensitivity was examined with insulin tolerance testing and homeostasis model assessment for insulin resistance. Energy metabolism was monitored in a metabolic chamber. Mitochondrial function was investigated in brown adipocytes and skeletal muscle in the mice.RESULTSOn the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice. Fasting blood glucose, fasting insulin, and insulin tolerance were all preserved in the treated mice. Body fat content was maintained at 10% without a reduction in food intake. Adaptive thermogenesis and fatty acid oxidation were enhanced. An increase in mitochondrial function and biogenesis was observed in skeletal muscle and brown fat. The type I fiber was enriched in skeletal muscle. Peroxisome proliferator–activated receptor-γ coactivator-1α expression was elevated at mRNA and protein levels. AMP kinase and p38 activities were elevated. In the obese mice, supplementation of butyrate led to an increase in insulin sensitivity and a reduction in adiposity.CONCLUSIONSDietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse. The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.

Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293: E1118-E1128, 2007. First published July 31, 2007; doi:10.1152/ajpendo.00435.2007.-Chronic inflammation and reduced adiponectin are widely observed in the white adipose tissue in obesity. However, the cause of the changes remains to be identified. In this study, we provide experimental evidence that hypoxia occurs in adipose tissue in obese mice and that adipose hypoxia may contribute to the endocrine alterations. The adipose hypoxia was demonstrated by a reduction in the interstitial partial oxygen pressure (PO2), an increase in the hypoxia probe signal, and an elevation in expression of the hypoxia response genes in ob/ob mice. The adipose hypoxia was confirmed in dietary obese mice by expression of hypoxia response genes. In the adipose tissue, hypoxia was associated with an increased expression of inflammatory genes and decreased expression of adiponectin. In dietary obese mice, reduction in body weight by calorie restriction was associated with an improvement of oxygenation and a reduction in inflammation. In cell culture, inflammatory cytokines were induced by hypoxia in primary adipocytes and primary macrophages of lean mice. The transcription factor NF-B and the TNF-␣ gene promoter were activated by hypoxia in 3T3-L1 adipocytes and NIH3T3 fibroblasts. In addition, adiponectin expression was reduced by hypoxia, and the reduction was observed in the gene promoter in adipocytes. These data suggest a potential role of hypoxia in the induction of chronic inflammation and inhibition of adiponectin in the adipose tissue in obesity.partial oxygen pressure; obesity; type 2 diabetes; insulin resistance IN OBESITY, chronic inflammation and reduced adiponectin in the white adipose tissue (WAT) contribute to pathogenesis of insulin resistance, which links obesity to many complications, such as type 2 diabetes and cardiovascular diseases (23,24,30). The chronic inflammation is indicated by an increased expression of proinflammatory cytokines and elevated infiltration of macrophages into adipose tissue. Of the proinflammatory cytokines, TNF-␣ and IL-6 reduce insulin sensitivity and impair the homeostasis of lipid and glucose metabolism. Monocyte chemoattractant protein-1 (MCP-1) promotes macrophage infiltration into adipose tissue. Although expression of these cytokines is increased in adipose tissue of obese subjects, it is not clear what induces expression of these inflammatory cytokines in obesity. A decrease in adiponectin (ACRP30) production contributes to pathogenesis of insulin resistance (23). However, it remains to be investigated what obesityassociated factor leads to suppression of adiponectin.Systemic hypoxia is associated with insulin resistance in human and animal. In patients with obstructive sleep apnea or sleep-disordered breathing, intermittent hypoxia is associated with a high risk for insulin resistance (...

A facile method for the synthesis of size-and shape-controlled CuInS 2 semiconductor nanocrystals was developed by thermolysis of a mixed solution of CuAc, In(Ac) 3 (molar ratio of CuAc to In(Ac) 3 ) 1:1) and dodecanethiol in noncoordinating solvent 1-octadecene (ODE) at 240 °C. CuInS 2 nanoparticles with size of 2 to ∼5 nm and nanorods with aspect ratio of 1 to ∼3 were obtained by adjusting the reaction parameters such as temperature and time. The as-prepared nanoparticles were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy, selected area electron diffraction spectroscopy, inductively coupled plasma atomic emission spectroscopy, UV-vis absorption, and photoluminescence (PL) spectroscopy. The nanoparticle solutions exhibit tunable absorption and PL spectra with the absorption edge ranging from 550 to 750 nm and PL emission peaks from 600 to 750 nm, indicating a strong size-dependent quantum confinement effect. Optical measurements of the CuInS 2 nanoparticles demonstrated that their optical properties are related to donor-acceptor defects, size-dependent quantum confined effects, and surface defects. The PL decay curve of CuInS 2 nanoparticles has a triple exponential characteristic with lifetimes of 4-12, 28-60, and 140-300 ns, respectively, and the PL emission with the longest lifetime (140-300 ns) occupied 40-80% of the PL emission of the samples. These results imply that the room-temperature PL emission of CuInS 2 nanoparticles involves three types of recombination: band exciton recombination, surface-related recombination, and donor-acceptor defects recombination. Among them, the PL emission from donor-acceptor defects occupied a large amount.

Insulin resistance contributes importantly to the pathophysiology of type 2 diabetes mellitus. One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor B kinase (IKK) complex. However, the precise molecular mechanisms by which IKK may contribute to the development of insulin resistance are not well understood. In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser 307 (equivalent to Ser 312 in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-␣ or calyculin A treatment that paralleled surrogate markers for IKK activation. The phosphorylation of human IRS-1 at Ser 312 in response to tumor necrosis factor-␣ was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J 2 as well as in cells derived from IKK knock-out mice. We observed interactions between endogenous IRS-1 and IKK in intact cells using a co-immunoprecipitation approach. Moreover, this interaction between IRS-1 and IKK in the basal state was reduced upon IKK activation and increased serine phosphorylation of IRS-1. Data from in vitro kinase assays using recombinant IRS-1 as a substrate were consistent with the ability of IRS-1 to function as a direct substrate for IKK with multiple serine phosphorylation sites in addition to Ser 312 . Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser 312 (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.Many factors implicated in the development of insulin resistance such as TNF-␣ 1 (1, 2), free fatty acids (3, 4), and serine phosphatase inhibitors (5, 6) are able to activate the inhibitor B kinase (IKK) complex and its downstream effector, NFB (7-10). Interestingly, insulin-sensitizing drugs such as thiazolidinediones inhibit NFB activity (11). Adiponectin, a cytokine secreted by adipose cells whose plasma levels are negatively correlated with insulin resistance (12), inhibits IKK activity in cells (13). Moreover, diet-induced insulin resistance is ameliorated in IKK2-deficient mice (14). Because IKK and NFB are major components of the intracellular inflammatory pathway, a cross-talk between metabolic and inflammatory signaling pathways may play an important role in the development of insulin resistance and the pathophysiology of major public health problems such as diabetes and obesity. However, molecular mechanisms by which IKK may specifically interact with metabolic insulin signaling pathways are not well understood. IKK is a serine kinase that controls the activation of NFB, a ubiquitous transcription factor closely associated with inflammation (15-18). In addition to inflammation, NF...

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.

Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetic patients. In study A, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (0.5 g t.i.d.) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (HbA 1c ; from 9.5% ± 0.5% to 7.5% ± 0.4%, P<0.01), fasting blood glucose (FBG; from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L, P<0.01), postprandial blood glucose (PBG; from 19.8 ± 1.7 to 11.1 ± 0.9 mmol/L, P<0.01) and plasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03 mmol/L, P<0.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering FBG and PBG from one week to the end of the trial. HbA 1c decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced by 28.1% and 44.7% (P<0.001), respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly as well. During the trial, 20 (34.5%) patients suffered from transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Toll-like receptors (TLRs)1 play a critical role in inducing innate immune responses in mammals by recognizing conserved pathogen-associated molecular patterns of bacteria (1-4). So far, 10 human TLRs have been cloned (5-10). The TLR agonists include lipopolysaccharide (LPS) for TLR4, peptidoglycan for TLR2 and TLR6, double-stranded RNA for TLR3, flagellin for TLR5, and imidazoquinolines and unmethylated CpG motifs in bacterial DNA for TLR7 and TLR9, respectively (3,(11)(12)(13)(14). TLR4 can be activated by nonbacterial agonists such as HSP60, fibronectin, Taxol, respiratory syncytical virus coat protein, and saturated fatty acids (15)(16)(17)(18)(19)(20).TLRs are type I transmembrane receptors characterized by the presence of extracellular leucine-rich repeat motifs and a cytoplasmic Toll/interleukin-1 receptor (TIR) homology domain, which is required for the activation of downstream signaling pathways leading to the activation of nuclear factor-B (NFB) (21). Myeloid differentiation factor-88 (MyD88) is known as an immediate downstream adaptor molecule that interacts directly with the TIR domain of TLRs (22,23). MyD88 recruits interleukin-1 receptor-associated kinase (IRAK) and tumor necrosis factor receptor-associated factor-6 (TRAF6), leading to activation of NFB and mitogenactivated protein kinases (MAPKs) (24,25). Activation of NFB leads to the expression of target genes, including cyclooxygenase-2 (COX-2) and cytokines. TIR domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) is another adaptor molecule cooperating with MyD88, leading to activation of . TIR domaincontaining adaptor inducing interferon-␤ (TRIF)/TIR domain-containing adaptor molecule-1 (TICAM-1) has been reported as another adaptor molecule responsible for the MyD88-independent signaling pathway derived from TLR3, leading to the activation of interferon regulatory factor-3 and the expression of interferon-␤ (29 -31). Thus, individual TLR agonist can activate different downstream signaling pathways,