The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

/pdf/inflammatory-mechanisms-in-obesity-4zcumnwrzk.pdf

Inflammatory Mechanisms in Obesity

Malonyl-coenzyme A (malonyl-CoA), generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the regulation of energy homeostasis. Here, we show that Acc2-/- mutant mice have a normal life span, a higher fatty acid oxidation rate, and lower amounts of fat. In comparison to the wild type, Acc2-deficient mice had 10- and 30-fold lower levels of malonyl-CoA in heart and muscle, respectively. The fatty acid oxidation rate in the soleus muscle of the Acc2-/- mice was 30% higher than that of wild-type mice and was not affected by addition of insulin; however, addition of insulin to the wild-type muscle reduced fatty acid oxidation by 45%. The mutant mice accumulated 50% less fat in their adipose tissue than did wild-type mice. These results raise the possibility that pharmacological manipulation of ACC2 may lead to loss of body fat in the context of normal caloric intake.

https://science.sciencemag.org/content/sci/291/5513/2613.full.pdf

Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2.

Pro-inflammatory cytokines: The link between obesity and osteoarthritis.

Biodiesel is a clean-burning fuel produced from grease, vegetable oils, or animal fats. Biodiesel is produced by transesterification of oils with short-chain alcohols or by the esterification of fatty acids. The transesterification reaction consists of transforming triglycerides into fatty acid alkyl esters, in the presence of an alcohol, such as methanol or ethanol, and a catalyst, such as an alkali or acid, with glycerol as a byproduct. Because of diminishing petroleum reserves and the deleterious environmental consequences of exhaust gases from petroleum diesel, biodiesel has attracted attention during the past few years as a renewable and environmentally friendly fuel. Since biodiesel is made entirely from vegetable oil or animal fats, it is renewable and biodegradable. The majority of biodiesel today is produced by alkali-catalyzed transesterification with methanol, which results in a relatively short reaction time. However, the vegetable oil and alcohol must be substantially anhydrous and have a low free fatty acid content, because the presence of water or free fatty acid or both promotes soap formation. In this article, we examine different biodiesel sources (edible and nonedible), virgin oil versus waste oil, algae-based biodiesel that is gaining increasing importance, role of different catalysts including enzyme catalysts, and the current state-of-the-art in biodiesel production.

/pdf/biodiesel-production-current-state-of-the-art-and-challenges-28amo4npwv.pdf

Biodiesel production--current state of the art and challenges.

All plant cells produce fatty acids from acetyl-CoA by a common pathway localized in plastids. Although the biochemistry of this pathway is now well understood, much less is known about how plants control the very different amounts and types of lipids produced in different tissues. Thus, a central challenge for plant lipid research is to provide a molecular understanding of how plants regulate the major differences in lipid metabolism found, for example, in mesophyll, epidermal, or developing seed cells. Acetyl-CoA carboxylase (ACCase) is one control point that regulates rates of fatty acid synthesis. However, the biochemical modulators that act on ACCase and the factors that in turn control these modulators are poorly understood. In addition, little is known about how the expression of genes involved in fatty acid synthesis is controlled. This review evaluates current knowledge of regulation of plant fatty metabolism and attempts to identify the major unanswered questions.

Regulation of fatty acid synthesis

Acetyl-CoA carboxylase, the rate-limiting enzyme in the biogenesis of long-chain fatty acids, is regulated by phosphorylation and dephosphorylation. The major phosphorylation sites that affect carboxylase activity and the specific protein kinases responsible for phosphorylation of different sites have been identified. A form of acetyl-CoA carboxylase that is independent of citrate for activity occurs in vivo. This active form of carboxylase becomes citrate-dependent upon phosphorylation under conditions of reduced lipogenesis. Therefore, phosphorylation-dephosphorylation of acetyl-CoA carboxylase is the enzyme's primary short-term regulatory mechanism; this control mechanism together with cellular metabolites such as CoA, citrate, and palmitoyl-CoA serves to fine-tune the synthesis of long-chain fatty acids under different physiological conditions.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.3.11.2570725

Role of reversible phosphorylation of acetyl-CoA carboxylase in long-chain fatty acid synthesis.

Physiological regulation of acetyl-CoA carboxylase gene expression: effects of diet, diabetes, and lactation on acetyl-CoA carboxylase mRNA.

Preparation of functional acetyl-CoA carboxylase mRNA from rat mammary gland

Tumour necrosis factor (TNF) inhibits the accumulation of acetyl CoA carboxylase (ACC) mRNA by decreasing the rate of ACC gene transcription. The ACC mRNA species found in 30A5 cells are generated from promoter II and TNF inhibits the accumulation of class 2 type mRNAs. By using 5' deletion mutants of promoter II fused to the bacterial chloramphenicol acetyltransferase (CAT) gene, the DNA mobility shift assay and the DNase I footprinting assay, the authors have identified the 30 bp from −389 to −359 as the TNF responsive element in promoter II. TNF treatment causes a decrease in the binding activity of nuclear protein(s) specific to the TNF responsive element. When the fragment containing the TNF responsive element was incorporated into the thymidine kinase promoter, the chimeric gene exhibited TNF induced inhibition of expression.

/pdf/sequences-of-acetyl-coa-carboxylase-promoter-for-tumour-1dhmnun2su.pdf

Sequences of acetyl CoA carboxylase promoter for tumour necrosis factor action.

Improvements in production of cDNA libraries in lambda gtll. Detection of ligation inhibitor and separation of cDNA from free linkers.

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