Chemerin regulates formation and function of brown adipose tissue: Ablation results in increased insulin resistance with high fat challenge and aging.

Apart from its role in inflammation and immunity, chemerin is also involved in white adipocyte biology. To study the role of chemerin in adipocyte metabolism, we examined the function of chemerin in brown adipose tissue. Brown and white adipocyte precursors were differentiated into adipocytes in the presence of Chemerin siRNA. Chemerin-deficient (Chem-/- ) mice were compared to wild-type mice when fed a high-fat diet. Chemerin is expressed during brown adipocyte differentiation and knock down of chemerin mRNA results in decreased brown adipocyte differentiation with reduced fatty acid uptake in brown adipocytes. Chem-/- mice are leaner than wild-type mice but gain more weight when challenged with high-fat diet feeding, resulting in a larger increase in fat deposition. Chem-/- mice develop insulin resistance when on a high-fat diet or due to age. Brown adipose depots in Chem-/- mice weigh more than in wild-type mice, but with decreased mitochondrial content and function. Compared to wild-type mice, male Chem-/- mice have decreased oxygen consumption, CO2 production, energy expenditure, and a lower respiratory exchange ratio. Additionally, body temperature of Chem-/- mice is lower than that of wild-type mice. These results revealed that chemerin is expressed during brown adipocyte differentiation and has a pivotal role in energy metabolism through brown adipose tissue thermogenesis.

Plasma membrane cholesterol trafficking in steroidogenesis.

Cholesterol is an important component of plasma membranes (PMs) and the precursor of all steroid hormones. In steroidogenic tissues, upon hormone stimulation, there is a rapid transfer of cholesterol to the mitochondria, which is the site of the initial step in steroidogenesis. In the current study, we examined PM cholesterol trafficking for steroidogenesis. In a mitochondrial reconstitution assay, adrenal PMs supported steroidogenesis in the absence of additional transport proteins. Depletion of cholesterol in PMs by 50% eliminated the membranes' ability to support steroidogenesis in vitro and reduced steroid production in intact Y1 adrenocortical cells. Syntaxin (STX)-5 and α-soluble N-ethylmaleimide-sensitive factor attachment protein (α-SNAP) are enriched in adrenal PMs, and adrenocorticotropic hormone treatment of rats recruited STX5 and α-SNAP to adrenal PMs and mitochondria. Immunodepletion of STX5 and α-SNAP from PMs decreased steroidogenesis supported by PMs in vitro. Protease digestion of PMs decreased, whereas recombinant STX5 or α-SNAP restored, the PMs' ability to support steroidogenesis. Knockdown of either STX5 or α-SNAP in Y1 cells decreased stimulated steroidogenesis. These results indicate that STX5 and α-SNAP facilitate cholesterol trafficking from PMs to mitochondria for adrenal steroid synthesis and underscore the importance of vesicular trafficking of PM cholesterol for steroidogenesis.-Deng, B., Shen, W.-J., Dong, D., Azhar, S., Kraemer, F. B. Plasma membrane cholesterol trafficking in steroidogenesis.

Ophiopogonin D attenuates doxorubicin-induced autophagic cell death by relieving mitochondrial damage in vitro and in vivo.

It has been reported that ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from Ophiopogon japonicas, promotes antioxidative protection of the cardiovascular system. However, it is unknown whether OP-D exerts protective effects against doxorubicin (DOX)-induced autophagic cardiomyocyte injury. Here, we demonstrate that DOX induced excessive autophagy through the generation of reactive oxygen species (ROS) in H9c2 cells and in mouse hearts, which was indicated by a significant increase in the number of autophagic vacuoles, LC3-II/LC3-I ratio, and upregulation of the expression of GFP-LC3. Pretreatment with OP-D partially attenuated the above phenomena, similar to the effects of treatment with 3-methyladenine. In addition, OP-D treatment significantly relieved the disruption of the mitochondrial membrane potential by antioxidative effects through downregulating the expression of both phosphorylated c-Jun N-terminal kinase and extracellular signal-regulated kinase. The ability of OP-D to reduce the generation of ROS due to mitochondrial damage and, consequently, to inhibit autophagic activity partially accounts for its protective effects in the hearts against DOX-induced toxicity.

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

OBJECTIVE: SNAP-25 is one of the key proteins involved in formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that are at the core of hormonal secretion and synaptic transmission. Altered expression or function of SNAP-25 can contribute to the development of neuropsychiatric and metabolic disease. A dominant negative (DN) I67T missense mutation in the b-isoform of SNAP-25 (DN-SNAP25mut) mice leads to abnormal interactions within the SNARE complex and impaired exocytotic vesicle recycling, yet the significance of this mutation to any association between the central nervous system and metabolic homeostasis is unknown. METHODS: Here we explored aspects of metabolism, steroid hormone production and neurobehavior of DN-SNAP25mut mice. RESULTS: DN-SNAP25mut mice displayed enhanced insulin function through increased Akt phosphorylation, alongside increased adrenal and gonadal hormone production. In addition, increased anxiety behavior and beigeing of white adipose tissue with increased energy expenditure were observed in mutants. CONCLUSIONS: Our results show that SNAP25 plays an important role in bridging central neurological systems with peripheral metabolic homeostasis, and provide potential insights between metabolic disease and neuropsychiatric disorders in humans.

Aging Tregs need DCAFinating.

Loss of DCAF1 and resulting ROS leads to Treg aging and inflammation.

The role of miRNAs in regulating adrenal and gonadal steroidogenesis.

miRNAs are endogenous noncoding single-stranded small RNAs of ~22 nucleotides in length that post-transcriptionally repress the expression of their various target genes. They contribute to the regulation of a variety of physiologic processes including embryonic development, differentiation and proliferation, apoptosis, metabolism, hemostasis and inflammation. In addition, aberrant miRNA expression is implicated in the pathogenesis of numerous diseases including cancer, hepatitis, cardiovascular diseases and metabolic diseases. Steroid hormones regulate virtually every aspect of metabolism, and acute and chronic steroid hormone biosynthesis is primarily regulated by tissue-specific trophic hormones involving transcriptional and translational events. In addition, it is becoming increasingly clear that steroidogenic pathways are also subject to post-transcriptional and post-translational regulations including processes such as phosphorylation/dephosphorylation, protein‒protein interactions and regulation by specific miRNAs, although the latter is in its infancy state. Here, we summarize the recent advances in miRNA-mediated regulation of steroidogenesis with emphasis on adrenal and gonadal steroidogenesis.

Molecular changes in hepatic metabolism in ZDSD rats-A new polygenic rodent model of obesity, metabolic syndrome, and diabetes.

In recent years, the prevalence of obesity, metabolic syndrome and type 2 diabetes is increasing dramatically. They share pathophysiological mechanisms and often lead to cardiovascular diseases. The ZDSD rat was suggested as a new animal model to study diabetes and the metabolic syndrome. In the current study, we have further characterized metabolic and hepatic gene expression changes in ZDSD rats. Immuno-histochemical staining of insulin and glucagon on pancreas sections of ZDSD and control SD rats revealed that ZDSD rats have severe damage to their islet structures as early as 15 weeks of age. Animals were followed till they were 26 weeks old, where they exhibited obesity, hypertension, hyperglycemia, dyslipidemia, insulin resistance and diabetes. We found that gene expressions involved in glucose metabolism, lipid metabolism and amino acid metabolism were changed significantly in ZDSD rats. Elevated levels of ER stress markers correlated with the dysregulation of hepatic lipid metabolism in ZDSD rats. Key proteins participating in unfolded protein response pathways were also upregulated and likely contribute to the pathogenesis of dyslipidemia and insulin resistance. Based on its intact leptin system, its insulin deficiency, as well as its timeline of disease development without diet manipulation, this insulin resistant, dyslipidemic, hypertensive, and diabetic rat represents an additional, unique polygenic animal model that could be very useful to study human diabetes.

Creosote bush-derived NDGA attenuates molecular and pathological changes in a novel mouse model of non-alcoholic steatohepatitis (NASH).

Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic steatosis, fibrosis, inflammation, ER stress, oxidative stress, and liver injury. NDGA attenuated these metabolic abnormalities as well as hepatic steatosis and fibrosis together with attenuated expression of genes encoding fibrosis, progenitor and macrophage markers with no effect on the levels of mRNAs for lipogenic enzymes. NDGA increased expression of fatty acid oxidation genes. In conclusion, NDGA exerts anti-NASH/anti-fibrotic actions and raises the therapeutic potential of NDGA for treatment of NASH patients with fibrosis and other associated complications.

Tissue-Specific Ablation of ACSL4 Results in Disturbed Steroidogenesis.

ACSL4 is a member of the ACSL family that catalyzes the conversion of long-chain fatty acids to acyl-coenzyme As, which are essential for fatty-acid incorporation and utilization in diverse metabolic pathways, including cholesteryl ester synthesis. Steroidogenic tissues such as the adrenal gland are particularly enriched in cholesteryl esters of long-chain polyunsaturated fatty acids, which constitute an important pool supplying cholesterol for steroid synthesis. The current studies addressed whether ACSL4 is required for normal steroidogenesis. CYP11A1 promoter‒mediated Cre was used to generate steroid tissue‒specific ACSL4 knockout (KO) mice. Results demonstrated that ACSL4 plays an important role in adrenal cholesteryl ester formation, as well as in determining the fatty acyl composition of adrenal cholesteryl esters, with ACSL4 deficiency leading to reductions in cholesteryl ester storage and alterations in cholesteryl ester composition. Statistically significant reductions in corticosterone and testosterone production, but not progesterone production, were observed in vivo, and these deficits were accentuated in ex vivo and in vitro studies of isolated steroid tissues and cells from ACSL4-deficient mice. However, these effects on steroid production appear to be due to reductions in cholesteryl ester stores rather than disturbances in signaling pathways. We conclude that ACSL4 is dispensable for normal steroidogenesis.

Profiling metabolic remodeling in PP2Acα deficiency and chronic pressure overload mouse hearts.

Our understanding of how metabolic switches occur in the failing heart is still limited. Here, we report the emblematic pattern of metabolic alternations in two different mouse models. PP2Acα deficient hearts exhibited a dramatic decrease in the levels of mRNA encoding for transporters and enzymes involved in glucose utilization, which compensated by higher expression levels of genes controlling fatty acid utilization. These features were partly reproduced in cultured PP2Acα KD cardiomyocytes. Equivalently, a decrease in the expression of most of the transporters and enzymes controlling both glucose and fatty acid metabolism were observed in TAC model.