Featured Articles

Volume 23 | May 2019

Dysregulated transmethylation leading to HCC compromises redox homeostasis and glucose formationThe incidence of hepatocellular carcinoma (HCC) is increasing. Dysregulated metabolism is an important contributor to the pathogenesis of cancer. Experimental models suggest that impeding glucose production promotes HCC. The role of liver glycine N-methyltransferase (GNMT) in the relationship between glucose control and HCC is of particular interest. GNMT-null mice develop HCC by eight months of age, suggesting a causal role in tumorigenesis. Hughey et al. studied the relationship of GNMT action and glucose production to HCC formation. The results show that the lack of GNMT reduces glucose production. Reduced glucose production is coupled to impaired NAD+ synthesis and salvage. A decline in NAD+ availability may redirect the flux of glucose precursors to pathways that regulate tumorigenesis.

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The pseudokinase MLKL regulates hepatic insulin sensitivity Inflammation and cell death contribute to the development of type 2 diabetes (T2D). Necroptosis, a recently characterized necrosis integrated with the extrinsic apoptosis pathway, is widely viewed as a highly proinflammatory mode of cell death. The pseudokinase MLKL is a key protein in necroptosis. However, the involvement of necroptotic markers in insulin resistance and T2D remains unclear. Xu, Du, and colleagues show that the loss of MLKL in mice prevents obesity-induced insulin resistance and glucose intolerance. These findings reveal a role of MLKL in insulin sensitivity and suggest the potential involvement of necroptotic regulators in the physiopathology of T2D.

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Tim-3 aggravates podocyte injury in diabetic nephropathy Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. Macrophages are the most abundant immune cells in the diabetic kidney. T cell immunoglobulin domain and mucin domain-3 (Tim-3) has diverse regulatory roles in macrophages. Yang et al. demonstrate that the immune checkpoint molecule Tim-3 accelerates podocyte injury, which aggravates the progression of DN by triggering the NF-κB/TNF-α signaling pathway in macrophages.

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Foregut tyrosine metabolism in glucose tolerancePancreatic β-cells integrate several different external signals to finetune the release of insulin and thus accurately regulate blood glucose levels. The foregut is the major source of circulating dopamine (DA) and L-DOPA, which are synthesized from tyrosine. DA and L-DOPA might limit glucose-stimulated insulin secretion (GSIS). Korner, Cline, et al. provide proof-of-principle evidence for the existence of a postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of GSIS as proposed by the anti-incretin hypothesis.

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RYGB reprograms enterocyte triglyceride metabolism Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) is currently the most effective treatment for obesity and its related comorbidities. One important mechanism of action is a rapid and long-lasting reduction of plasma triglyceride (TG) levels. How RYGB decreases plasma TG levels, however, is unclear. Kaufman et al. reveal substantial RYGB-induced changes in how enterocytes handle lipids, including TG absorption, reesterification, storage in lipid droplets, and oxidation. These changes likely contribute to the RYGB-induced improvement in plasma TG levels.

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Brown fat organogenesis and maintenance requires AKT1 and AKT2Strategies to increase brown adipose tissue (BAT) amount and/or function are being considered as therapeutic strategies to fight metabolic diseases. Thus, understanding BAT development is of high clinical relevance. Using mouse genetics, Sanchez-Gurmaches and colleagues define distinct and overlapping functions for AKT1 and AKT2 in brown and white adipose tissue development and show that they are largely dispensable for skeletal muscle development.

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Pirt deficiency has female-specific effects on energy metabolismBrown adipose tissue (BAT) thermogenesis increases with prolonged exposure to cold, enabling mammals to maintain core body temperature. There is evidence to suggest direct cold-sensing by brown adipocytes via transient receptor potential melastatin 8 (TRPM8). Phosphoinositide interacting regulator of TRPs (Pirt) is an endogenous regulator of TRP channels. Jall and colleagues report that Pirt deficient female mice have an increased body weight and impaired glucose tolerance. This increased susceptibility to develop obesity and glucose intolerance is abrogated in the presence of a high-fat, high-sugar diet. Also, the authors reveal that Pirt is dispensable for TRPM8-induced BAT thermogenesis in vivo.

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RORα deletion does not affect the metabolic susceptibility to western style dietThe incidence of obesity and associated metabolic disorders increase worldwide. Accumulating evidence points towards nuclear receptor (NR) transcription factors as potential treatment targets. The retinoic acid-related orphan receptor α (RORα) is a NR that has been implicated in the regulation of a wide variety of metabolic pathways. Molinaro et al. generated a liver-specific RORα deficient mouse strain that was metabolically phenotyped on both chow and western-style diet (WSD). Their data show that the deletion of RORα in the liver does not affect glucose or lipid metabolism during WSD in mice. Further studies testing the role of liver RORα or the double RORα and RORγ deletion in different dietary settings are needed to further elucidate the role of RORα in obesity and metabolic disorders.

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Perm1 shapes skeletal muscle responses to endurance exercise trainingSkeletal muscle plays key roles in metabolic homeostasis and whole-body energy expenditure. Endurance exercise training remodels skeletal muscle by activating signaling pathways and regulating transcription factors. Perm1, a recently identified protein, is selectively expressed in skeletal and cardiac muscles. To gain insights into the cellular function of Perm1, Cho et al. searched for Perm1 interacting proteins. They show that Perm1 regulates physical activity-dependent CaMKII and MAPK p38 signaling and is important for a subset of exercise-induced responses. Their findings suggest that Perm1 modulates excitation-transcription coupling and shapes the response to endurance exercise.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Anne White, Jonathan Wray, Erika Harno
University of Manchester, UK
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