Metabolic Flexibility in Health and Disease

Goodpaster, Bret H.; Sparks, Lauren M.

doi:10.1016/j.cmet.2017.04.015

Cited by 639 publications

(598 citation statements)

References 123 publications

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“…Increased plasma FFA in OSA patients therefore reflects, at least transiently, excess FFA availability. In subjects with “flexible” metabolism [56], these shifts in substrate availability may be inconsequential or even beneficial. In fact, treatment of OSA with CPAP causes weight gain [57], suggesting that untreated OSA may increase the oxidation of at least a portion of mobilized FFA.…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Sleep apnea: An overlooked cause of lipotoxicity?

Younas

Jun

2017

Medical Hypotheses

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Obstructive sleep apnea (OSA) is a common sleep disorder associated with diabetes and cardiovascular disease. However, the mechanisms by which OSA causes cardiometabolic dysfunction are not fully elucidated. OSA increases plasma free fatty acids (FFA) during sleep, reflecting excessive adipose tissue lipolysis. In animal studies, intermittent hypoxia simulating OSA also increases FFA, and the increase is attenuated by beta-adrenergic blockade. In other contexts, excessive plasma FFA can lead to ectopic fat accumulation, insulin resistance, vascular dysfunction, and dyslipidemia. Herein, we propose that OSA is a cause of excessive adipose tissue lipolysis contributing towards systemic “lipotoxicity”. Since visceral and upper-body obesity contributes to OSA pathogenesis, OSA-induced lipolysis may further aggravate the consequences of this metabolically harmful state. If this hypothesis is correct, then OSA may represent a reversible risk factor for cardio-metabolic dysfunction, and this risk might be mitigated by preventing OSA-induced lipolysis during sleep.

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Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Sleep apnea: An overlooked cause of lipotoxicity?

Younas

Jun

2017

Medical Hypotheses

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“…Overweight and obesity are characterized by increased lipid accumulation in adipocytes, whereas weight loss is characterized by reduced lipid accumulation in AT (Eriksson-Hogling et al, 2015;Goodpaster and Sparks, 2017). Obesity is strongly correlated with metabolic disease -for every kg increase in body weight, diabetes rates increase linearly (Haffner, 2006).…”

Section: Introductionmentioning

confidence: 99%

Adipose morphology and metabolic disease

Tandon

Wafer

Minchin

2018

Journal of Experimental Biology

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Adipose morphology is defined as the number and size distribution of adipocytes (fat cells) within adipose tissue. Adipose tissue with fewer but larger adipocytes is said to have a 'hypertrophic' morphology, whereas adipose with many adipocytes of a smaller size is said to have a 'hyperplastic' morphology. Hypertrophic adipose morphology is positively associated with insulin resistance, diabetes and cardiovascular disease. By contrast, hyperplastic morphology is associated with improved metabolic parameters. These phenotypic associations suggest that adipose morphology influences risk of cardiometabolic disease. Intriguingly, monozygotic twin studies have determined that adipose morphology is in part determined genetically. Therefore, identifying the genetic regulation of adipose morphology may help us to predict, prevent and ameliorate insulin resistance and associated metabolic diseases. Here, we review the current literature regarding adipose morphology in relation to: (1) metabolic and medical implications; (2) the methods used to assess adipose morphology; and (3) transcriptional differences between morphologies. We further highlight three mechanisms that have been hypothesized to promote adipocyte hypertrophy and thus to regulate adipose morphology.

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“…26,29,32 We speculate that Gpr27 regulates acylcarnitine metabolism and that the subsequent accumulation of acylcarnitines influences insulin-mediated glucose homeostasis ( Figure 4F-G). 52 Hence, it will be important to determine if loss of gpr27 affects the rates of fatty acid and glucose oxidation, in addition to fuel selection. For instance, lipid overload has been linked to oxidative stress, reduced mitochondrial respiratory capacity, and inhibition of glucose-coupled insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish

Nath

Chen

et al. 2019

FASEB j.

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G protein-coupled receptors (GPCRs) comprise the largest group of membrane receptors in eukaryotic genomes and collectively they regulate nearly all cellular processes.Despite the widely recognized importance of this class of proteins, many GPCRs remain understudied. G protein-coupled receptor 27 (Gpr27) is an orphan GPCR that displays high conservation during vertebrate evolution. Although, GPR27 is known to be expressed in tissues that regulate metabolism including the pancreas, skeletal muscle, and adipose tissue, its functions are poorly characterized. Therefore, to investigate the potential roles of Gpr27 in energy metabolism, we generated a whole body gpr27 knockout zebrafish line. Loss of gpr27 potentiated the elevation in glucose levels induced by pharmacological or nutritional perturbations. We next leveraged a mass spectrometry metabolite profiling platform to identify other potential metabolic functions of Gpr27. Notably, genetic deletion of gpr27 elevated medium-chain acylcarnitines, in particular C6-hexanoylcarnitine, C8-octanoylcarnitine, C9-nonanoylcarnitine, and C10-decanoylcarnitine, lipid species known to be associated with insulin resistance in humans. Concordantly, gpr27 deletion in zebrafish abrogated insulin-dependent Akt phosphorylation and glucose utilization. Finally, loss of gpr27 increased the expression of key enzymes in carnitine shuttle complex, in particular the homolog to the brain-specific isoform of CPT1C which functions as a hypothalamic energy senor. In summary, our findings shed light on the biochemical functions of Gpr27 by illuminating its role in lipid metabolism, insulin signaling, and glucose homeostasis. K E Y W O R D Scarnitine palmitoyltransferase I, G protein-coupled receptors, insulin resistance, lipid metabolism, metabolomic profiling * SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Nath AK, Ma J, Chen Z-Z, et al. Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish. The FASEB Journal.

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Metabolic Flexibility in Health and Disease

Cited by 639 publications

References 123 publications

Sleep apnea: An overlooked cause of lipotoxicity?

Sleep apnea: An overlooked cause of lipotoxicity?

Adipose morphology and metabolic disease

Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish

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