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Volume 25 | July 2019

Acute thyroxine-induced thermogenesis is independent of UCP1Hyperthyroidism is associated with an increased body temperature. The molecular nature of this has not been clarified although it is thought that the reason is activation of brown adipose tissue. In the brown fat cells, thermogenesis would occur via uncoupling-protein-1 (UCP1). To test this hypothesis, Dittner et al. have examined thyroid thermogenesis induced by peripherally administered thyroxine in wild-type mice and UCP1 knockout mice. The authors found that thyroid thermogenesis was independent of the presence of UCP1.

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SIRT3 controls brown fat thermogenesis by regulation upstream of UCP1Brown adipose tissue (BAT) is capable of thermogenesis via uncoupling protein 1 (UCP1) and has high expression of sirtuin 3 (SIRT3), a deacetylase in the mitochondria. Much of the acetylation that occurs in mitochondria is thought to occur nonenzymatically. SIRT3 appears to play a critical role in reversing these acetylations, which are generally thought to have an inhibitory effect on enzymatic activities. The findings of Sebaa et al. suggest that SIRT3 indirectly controls BAT thermogenesis by deacetylating and promoting the function of pathways upstream of UCP1.

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Noggin depletion in adipocytes promotes obesityNoggin is an extracellular inhibitor of bone morphogenetic proteins (BMPs), growth factors that regulate development and tissue differentiation through their influences on cell proliferation, lineage and migration. Blázquez-Medela and colleagues investigated whether Noggin has the ability to modulate adipose tissue and obesity. They deleted the Noggin gene in mouse adipocytes in vivo and found that Noggin deficiency promotes age-related whitening of brown adipose tissue and white adipose hypertrophy associated with obesity.

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Loss of GLP-1R and Y2R does not alter progression of obesity or response to RYGB surgeryRoux-en-Y gastric bypass (RYGB) results in large and sustained weight loss. It is thought that the beneficial effects of RYGB are mediated, at least in part, by the gut hormones GLP-1 and PYY. Boland, Mumphrey, et al. hypothesized that deleting both signaling pathways simultaneously in GLP1R/Y2R double knockout mice would significantly attenuate the effects of RYGB. Unexpectedly, however, combined loss of GLP-1R and Y2R signaling had only minor effects on body weight, fat mass, and glucose homeostasis. Furthermore, RYGB was just as effective in lowering body weight and adiposity as well as improving glucose tolerance and insulin sensitivity.

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Maternal Western-style diet affects offspring isletsThe Developmental Origins of Health and Disease (DOHaD) hypothesis states that the gestational and immediate postnatal environments influence long-term offspring health and play a role in adult disease etiology. Elsakr and colleagues used a well-established, non-human primate (NHP) model, the Japanese Macaque, to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring. Islets from offspring whose mothers had received WSD secreted more insulin in response to a glucose challenge ex vivo. Reduction of α-cell mass as a result of maternal WSD persists to three years of age even when offspring are weaned onto control diet.

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ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulationInsulin suppresses lipolysis in adipocytes. However, the mechanism for this is not well understood. ABHD15 displays several properties implicating it as having an important role in lipolysis. It is a member of the α/β-hydrolase family of proteins that includes several other lipolytic regulatory proteins. Stöckli, Zadoorian, et al. show that insulin-stimulated suppression of lipolysis is blocked in the absence of ABHD15 in adipocytes. ABHD15 knockout mice displayed elevated circulating free fatty acids upon fasting and in response to insulin. Furthermore, ABHD15 knockout mice showed increased liver triglycerides upon β-adrenergic receptor activation.

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JUND regulates pancreatic β cell survival JUND is a member of the Jun family of transcription factors. It has been previously linked to regulating oxidative stress in other cell types, but its role in β cells is unknown. Good et al. uncover JUND as a novel stress-responsive factor that is translationally upregulated in β cells during metabolic stress. Assessments of oxidative stress and apoptosis in primary islets as well as transcriptome analyses indicate that JUND promotes a maladaptive response in β cells during conditions associated with type 2 diabetes.

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Reduced insulin action in muscle not associated with defective insulin signalingEnergy metabolism in mammals is regulated by mechanisms that follow a clear diurnal rhythm. Assessing glucose metabolism and insulin action for any dysregulation relevant to the risk of developing type 2 diabetes at a single point in time therefore provides only a limited picture of the 24-hour physiology of glucose homeostasis. Small and colleagues investigated the relationship between circulating insulin, insulin signaling, and glucose metabolism in vivo over multiple points of the normal diurnal cycle. The results show that reduced glucose uptake in the muscle of high fat, high sugar-fed rats over the diurnal cycle was not associated with reduced Akt signaling.

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A sterol-regulated feedback loop modulates statin sensitivity in prostate cancerProstate cancer (PCa) is the most commonly diagnosed malignancy in men. Statins are clinically approved agents that are commonly prescribed for the management of high cholesterol, but more recently have been shown to possess anti-cancer properties. However, heterogeneous responses to statin exposure have been reported. Longo et al. investigated the conditions which may make PCa cells sensitive to statins. They report that inhibition of the sterol regulatory element-binding protein 2 potentiated statin-induced apoptosis in PCa cells that were relatively insensitive to statin as a single agent.

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A leptin receptor point mutation resulting in metabolic dysfunctions distinct from db/db miceLeptin plays a crucial role in controlling food intake and energy expenditure. Leptin receptor deficient (db/db) mice suffer from fat accumulation, massive obesity, and the development of diabetes due to excessive food intake. Piattini, Le Foll, and colleagues describe a novel spontaneous point mutation of the leptin receptor gene in mice, leading to a truncated protein. Partial responsiveness to leptin in homozygous mutants resulted in differences in the control of energy expenditure and the severity of diabetes compared to db/db mice, although the development of obesity was comparable to full KO mice.

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Gsα deficiency in the dorsomedial hypothalamus leads to obesity Gsα couples multiple receptors to intracellular cAMP generation. Germline inactivating Gsα mutations lead to obesity in humans and mice. Mice with brain-specific Gsα deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Chen et al. created mice with complete Gsα deficiency in the dorsomedial hypothalamus. These mice develop severe early-onset obesity associated with hyperphagia, along with decreases in energy expenditure. This is associated with impaired leptin signaling.

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Imaging adipose tissue browning using the TSPO-18kDa tracer [18F]FEPPAChemical stimulation with β3-adrenergic receptor agonists has been shown to induce browning in white adipose tissue (WAT), but determination of the quantity and location of this new beige fat mass is a challenge. The difference in mitochondrial abundance between WAT and beige fat suggests that an imaging agent able to quantify mitochondrial expression may be ideal for identifying beige fat mass. TSPO-18kDa (TSPO) is a five transmembrane domain protein located on the outer membrane of mitochondria, which may be detected using positron emission tomography (PET). Hartimath et al. tested the TSPO tracer [18F]FEPPAand found that it may be useful for detecting unstimulated beige adipocytes.

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Epigenetic regulation of diabetogenic adipose morphologyWhite adipose tissue (WAT) expands by increasing adipocyte number (hyperplasia) and size (hypertrophy). Their relative importance differs between individuals resulting in alternate adipose morphologies. Hypertrophic WAT is the pernicious morphology, which is associated with dyslipidemia, insulin resistance, and T2D. Kerr and colleagues tested whether WAT morphology is epigenetically regulated and performed CpG-methylome profiling on abdominal subcutaneous adipocytes from a large cohort of women. Their results support the notion that differential CpG-methylation in adipocytes is linked to hypertrophic WAT morphology predisposing to T2D.

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The best housing temperature to translate mouse experiments to humansTemperature is a key environmental variable that has various impacts on the physiology and health of all animals, including humans. Mice are currently the most widely used animal model for human disease and fundamental biology. Therefore, it is important to choose a housing temperature for mice that best mimics everyday human conditions; however, which temperature to choose is not trivial. Keijer and colleagues studied the oxygen consumption of C57BL/6 mice measured across the range of temperatures from 21.4 to 30.2 °C in order to find the best housing temperature. From their results, they conclude that 25.5 °C to 27.6 °C may be optimal for solitary housed mice and discuss this in the light of suggestions and results from other groups.

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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.



Daniela Cota
INSERM, Bordeaux, France
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