Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

The Ethylmalonyl-CoA Pathway for Methane-based Biorefineries: A Case Study of Using Methylosinus trichosporium OB3b, an Alpha-proteobacterial Methanotroph, for Producing 2-Hydroxyisobutyric Acid and 1,3-Butanediol from Methane

The ethylmalonyl-CoA pathway is one of three known anaplerotic pathways that replenish tricarboxylic acid cycle intermediates and plays a major role in the carbon metabolism of many alpha-proteobacteria including Methylosinus...

Structure, interactions and action of Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase

Biochemical and crystallographic studies on Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase (MtHIBADH), a member of the 3-hydroxyacid dehydrogenase superfamily, have been carried out. Gel filtration and blue native PAGE of MtHIBADH show that the enzyme is a dimer. The enzyme preferentially uses NAD+ as the cofactor and is specific to S-hydroxyisobutyric acid (HIBA). It can also use R-HIBA, l-serine and 3-hydroxypropanoic acid (3-HP) as substrates, but with much less efficiency. The pH optimum for activity is ∼11. Structures of the native enzyme, the holoenzyme, binary complexes with NAD+, S-HIBA, R-HIBA, l-serine and 3-HP and ternary complexes involving the substrates and NAD+ have been determined. None of the already known structures of HIBADH contain a substrate molecule at the binding site. The structures reported here provide for the first time, among other things, a clear indication of the location and interactions of the substrates at the active site. They also define the entrance of the substrates to the active site region. The structures provide information on the role of specific residues at the active site and the entrance. The results obtained from crystal structures are consistent with solution studies including mutational analysis. They lead to the proposal of a plausible mechanism of the action of the enzyme.

Case report: intermittent fasting and probiotic yogurt consumption are associated with reduction of serum alpha-N-acetylgalactosaminidase and increased urinary excretion of lipophilic toxicants

In this study, we describe the changes associated with three months of intermittent fasting and probiotic yogurt consumption in a 72-year-old marathon runner with chronic lymphocytic leukemia for a number of years. Serum alpha-N-acetylgalactosaminidase (nagalase), a marker of inflammation and cancer cell proliferation, was significantly decreased at the end of a three-month observation. These results are consistent with immune modulating properties of certain probiotics based on the fermentation of milk and colostrum. Urinary excretion of non-metal toxicants that accumulate in adipose tissue such as Perchlorate, N-acetyl(2-hydroxypropyl)cysteine (NAHP), 2,4-Dichlorophenoxyacetic acid, 3-Phenoxybenzoic acid (3PBA), N-acetyl phenyl cysteine (NAP), Phenylglycoxylic acid (PGO), Monoethylphthalate (MEP) and 2-Hydroxyisobutyric Acid (2HIB) was significantly increased. These results are consistent with the weight loss (5 Kg) associated with intermittent fasting and with the known features of probiotics as detoxification tools. Consistent with certain toxicants acting as endocrine disruptors, we observed an increased elimination of toxicants and a 33% decrease of serum Thyroid Stimulating Hormone (TSH), suggesting a trend toward normalization of thyroid function. These results support the hypothesis that a combination of intermittent fasting with the consumption of specific probiotic yogurts may lead to immune modulation, detoxification and other improvements.Abbreviations(NAHP)N-acetyl(2-hydroxypropyl)cysteine(3PBA)3-Phenoxybenzoic acid(NAP)Nacetyl phenyl cysteine(PGO)Phenylglycoxylic acid(MEP)Monoethylphthalate(2HIB)2-Hydroxyisobutyric Acid(TSH)Thyroid Stimulating Hormone(Dr. JB)Dr. Jerry Blythe(CLL)chronic lymphocytic leukemia(IRB)Institutional Review Board(GcMAF)Gc protein-derived Macrophage Activating Factor

Liquid chromatographic studies on the behaviour of Pu(III), Pu(IV) and Pu(VI) on a RP stationary phase in presence of α-Hydroxyisobutyric acid as a chelating agent

Since plutonium possesses multiple oxidation states which can coexist in solution, a method for the identification of these oxidation states is important to understand its chemical processes. Liquid chromatographic studies were carried out to compare the chromatographic behaviour of different oxidation states of Pu in presence of the eluent, α-hydroxyisobutyric acid (HIBA). The three oxidation states of Pu viz. Pu(III), Pu(IV) and Pu(VI) were separated under optimised conditions. It was seen that the presence of the complexing agent influences the equilibrium of Pu(III)/(IV) as well as Pu(IV)/(VI) systems. Pu(III) to Pu(IV) conversion was found to be enhanced by high pH and concentration of HIBA whereas a relatively low pH and high concentration of HIBA promotes the conversion of Pu(VI) to Pu(IV).