Featured Articles

Volume 24 | June 2019

Lipid metabolism biomarkers of BAT agingAging is a negative regulator of brown adipose tissue (BAT) formation and function. There is evidence that the effects of various lipid species on adipose tissue play a central role in the emergence of metabolic pathologies. However, very little is known about age-related changes of lipid metabolites in BAT, their involvement in BAT dysfunction and the contribution of this process to metabolic disorders. To identify functional lipid biomarkers of brown adipose tissue aging, Gohlke et al. combined metabolomic and proteomic analyses. These revealed that changes of several lipid classes and individual metabolite species correlate with adipose tissue aging. Among these, sphingolipids are significantly induced in aged BAT.

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Lipocalin 2 overexpression protects against decline in thermogenesis and metabolic deteriorationAging is the greatest risk factor for perturbations in metabolism including insulin resistance, dyslipidemia, and inflammation. Lipocalin 2 (Lcn2) is a circulating factor secreted from adipose tissue in response to obesity, inflammation, and nutrient/growth signals. Deis, Guo, et al. found that overexpression of Lcn2 in adipose tissue led to improved cold adaptation, altered whole-body energy expenditure with a trend towards fat oxidation, increased oxidative gene expression, decreased adipose tissue weight and adipocyte size, and decreased glucose/TG levels. Their results also suggest that overexpression of Lcn2 preserves adipose tissue function and prevents age-related glucose intolerance and liver lipid accumulation.

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Heterogeneity in the perirenal region suggests dormant brown adipose tissuePerirenal fat surrounds the kidney as well as the adrenal gland, which secretes epinephrine and norepinephrine in response to sympathetic activation. Jespersen, Feizi, et al. hypothesized that multilocular brown adipose tissue (BAT) would accumulate close to the adrenal gland and aimed to characterize the molecular differences between this fat compared to perirenal fat more distant from sources of norepinephrine. They demonstrate that most of the perirenal fat in adult humans consists of dormant BAT, while small amounts of adipocytes with a multilocular morphology and gene expression signature of active BAT, are present near regions where sympathetic activity is expected to be high.

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Deletion of Tcf7l2 promotes adipocyte hypertrophy and impaired glucose metabolism TCF7L2 is a component of the Wnt signaling pathway that is known to regulate metabolic disease in humans. Polymorphisms in Tcf7l2 are associated with type 2 diabetes. Geoghegan, Simcox, and colleagues conditionally deleted Tcf7l2 in adipocytes. They found that this leads to adipocyte hypertrophy and impaired glucose handling on a high-fat diet. This highlights that TCF7L2 has a role beyond development that extends to metabolic control in adipocytes.

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Ferritin regulates energy balance and thermogenesisIntracellular Fe redox activity is controlled by ferritin, a multimeric protein complex composed of variable ratios of ferritin light chain (FTL) and ferritin heavy chain (FTH). Blankenhaus, Braza, et al. report that global Fth deletion in adult mice leads to a profound disruption of organismal Fe metabolism and redox homeostasis, associated with failure to sustain energy expenditure and thermal homeostasis. Ferritin acts as a gatekeeper of organismal Fe metabolism, coupling nutritional Fe supply to organismal energy expenditure and thermoregulation.

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Point mutations in the PDX1 transactivation domain impair human β-cell development and functionThe transcription factor pancreas/duodenum homeobox protein 1 (PDX1) is one of the master regulators of pancreas development and β-cell function. In humans, several missense coding mutations in the PDX1 gene such as the P33T and C18R mutations in the transactivation domain have been associated with an increased risk for diabetes. The exact mechanisms by which these mutations contribute to diabetes predisposition are not understood. Wang et al. used patient-derived induced pluripotent stem cells to reveal mechanistic details of how these common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function.

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Novel eQTLs associated with type 2 diabetes Genome-wide association studies (GWAS) meta-analyses have revealed more than 200 loci associated with type 2 diabetes (T2D). Combining GWAS with expression data to produce expression quantitative trait loci (eQTLs) has become a powerful tool to shed light into the causative mechanisms of these genetic associations. Khamis, Canouil, and colleagues tested a total of 203 islet samples from European subjects with and without diabetes and provide a catalogue of cis-eQTLs associated with T2D.

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Discovering metabolic disease gene interactions by correlated effects on cellular morphology A plethora of disease relevant genetic loci have been identified by genetic association studies. Jiao and colleagues hypothesized that perturbing these loci/genes in adipocytes in vitro and assessing the effect on morphologic features would enable disease relevant functional annotation. Here, they demonstrate the utility of this approach in metabolic disease. They ablated 125 genes in human pre-adipocytes using CRISPR/CAS9 and profiled the effect on cellular morphology using morphologic similarity to identify mechanistic interactions between genes. They demonstrate that this morphometric approach is capable of surveying diverse cellular mechanisms by validating both a protein-protein interaction on the lipid droplet surface and a transcriptional regulatory interaction in the DNA.

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Dopamine neuronal protection by GHSR is independent of electric activityParkinson’s Disease (PD) is a neurodegenerative disease that appears when levels of dopamine (DA) in the substantia nigra (SN) display a 70-80% reduction. The etiology of PD is still elusive. Dln101 is a potential neuroprotective compound that targets the growth hormone secretagogue 1 receptor (GHSR). Stutz et al. evaluated Dln101 in comparison with ghrelin and investigated its GHSR-mediated effects that increase SN DA resilience. Although Dln101-mediated neuroprotection of SN DA cells was equivalent to that of ghrelin, its effect on electrical activity was very distinct despite the requirement of GHSR in mediating effects of both molecules.

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Dietary calories and lipids synergistically shape adipose tissue cellularityThe quantity and anatomical distribution of adipose tissue are key drivers of the metabolic syndrome. Obesity and abdominal visceral adiposity in particular are major risk factors for type 2 diabetes and cardiovascular disorders. Accumulating evidence suggests that childhood and adolescence are critical periods for shaping adipose tissue properties. However, the control of adipose progenitor proliferation and hyperplasia by dietary components are poorly understood. Meln, Wolff, et al. have investigated the role of excess calories and dietary lipids in adipose tissue proliferative growth in juvenile mice and found that both differentially and synergistically drive adipose tissue proliferative growth and the programming of the metabolic syndrome in childhood.

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Weight loss induces reactive astrogliosisAstrocytes and microglia respond to noxious stimuli by a process known as reactive gliosis (RG). RG is characterized by morphological changes such as increased cell size, enlarged, lengthened processes, and an increase in proliferation. Previously, in mice fed a high-fat diet (HFD) the number of reactive astrocytes and microglia in the arcuate nucleus (ARC) was increased. Harrison et al. have found that mice which are chronically obese after 22 weeks of HFD feeding display RG levels in the ARC comparable to levels seen in age-matched chow fed mice. Furthermore, profound weight loss results in an increase in ARC related astrocytic RG. However, whether or not reactive gliosis plays a role in chronic obesity, or rather in the acute adaptation to the dietary environment, remains to be fully understood.

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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.



Ildiko Kasza, Caroline Alexander
University of Wisconsin-Madison, United States
Referring article

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