Monounsaturated fat rapidly induces hepatic gluconeogenesis and whole-body insulin resistance

Sarabhai, Theresia; Kahl, S.; Szendroedi, Julia; Markgraf, Daniel F.; Zaharia, Oana‐Patricia; Barosa, Cristina; Herder, Christian; Wickrath, Frithjof; Bobrov, Pavel; Hwang, Jonghee; Jones, John G.; Roden, Michael

doi:10.1172/jci.insight.134520

Cited by 24 publications

(32 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Serum or plasma FGF21 levels were measured using the Quantikine ELISA Human FGF21 kit (R&D Systems, Minneapolis, coefficient of variation: Intra-Assay, 3.4%, Interassay 7.5%) according to the manufacturer's instructions. Our control values were similar to prior studies conducted in either serum or plasma with this kit, and its accuracy has been validated in both [45][46][47][48][49][50] . Samples were run in duplicate.…”

Section: Blood Fgf21 Measurementssupporting

confidence: 82%

FGF21 defines a potential cardio-hepatic signaling circuit in human heart failure

Sommakia

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundExtrinsic control of cardiac contractility and ultrastructure via neurohormonal signaling is well established, but how other organs regulate cardiomyocyte metabolism is less well understood. Fibroblast growth factor-21 (FGF21) a hormonal regulator of metabolism mainly produced in the liver and adipose tissue, is a prime candidate for such signaling.MethodsTo investigate this further, we examined blood and tissue obtained from human subjects with heart failure with reduced ejection fraction (HFrEF) at the time of left ventricular assist device (LVAD) implantation, and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.ResultsCirculating FGF21 levels were substantially elevated in HFrEF, compared to healthy subjects (HFrEF: 834.4 ± 101.8 pg/mL, n = 40; controls: 145.9 ± 28.6 pg/mL, n = 20, p = 5.5 × 10−8). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was low in failing and non-failing hearts, suggesting at least partial extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP and total bilirubin, markers of chronic cardiac and hepatic congestion.ConclusionsCirculating FGF21 levels are elevated in HFrEF. The liver is likely the main extracardiac source, and congestive hepatopathy, common in HFrEF, was likely the proximate signal leading to FGF21 elevations. This supports a model of venous congestion from cardiomyopathy driving hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardio-hepatic signaling circuit in human heart failure.

show abstract

Section: Blood Fgf21 Measurementssupporting

confidence: 82%

FGF21 defines a potential cardio-hepatic signaling circuit in human heart failure

Sommakia

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, the results of this short-term study in healthy humans cannot be necessarily extrapolated to chronic lipid oversupply or common insulin resistance of obesity and type 2 diabetes. Nevertheless, our approach represents an accepted compromise between optimal experimental and near-physiological conditions to allow for assessing acute metabolic changes [10][11][12].…”

Section: Discussionmentioning

confidence: 99%

“…Plasma FA analysis NEFA were analysed as their FA methyl esters (FAMEs) using GC-MS, as described in detail elsewhere [10,14]. Direct transesterification of all classes of lipids was carried out in a one-step reaction [14].…”

Section: Experimental Protocolmentioning

confidence: 99%

“…Serum concentrations of IL-6 and TNF-α were quantified using the respective Quantikine HS ELISA kits (R&D Systems/ BioTechne, Wiesbaden, Germany) [11]. During the basal period, R d was given as R d divided by the mean plasma insulin levels of the last 30 min of the respective period (+330 min to +360 min) [10]. Endogenous glucose production (EGP) was calculated from the rate of appearance (R a ) and was expressed as EGP × insulin levels of the last 30 min of basal period (+330 min to +360 min) [18].…”

Section: Experimental Protocolmentioning

confidence: 99%

See 1 more Smart Citation

Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis Energy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling. Methods In a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals. Results SAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05). Conclusions/interpretation Lipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling. Trial registration ClinicalTrials.gov.NCT01736202. Funding German Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research. Graphical abstract

show abstract

“…Hepatic glycogen synthesis and degradation fluxes are key components of systemic glucose homeostasis and are highly sensitive to the insulin/glucagon ratio. The application of in vivo 13 C MR to measure changes in hepatic glycogen during fasting and feeding has advanced our understanding of hepatic carbohydrate metabolism in subjects with insulin resistance, as well as in patients with diabetes [65][66][67][68][69]. Among other things, it revealed that while both hepatic glycogen deposition and degradation rates are significantly reduced in Type-1 diabetic subjects undergoing standard insulin therapy, these fluxes may be restored to normal with intensive insulin therapy [70,71].…”

Section: [56]mentioning

confidence: 99%

Non-Invasive Analysis of Human Liver Metabolism by Magnetic Resonance Spectroscopy

Jones

2021

Metabolites

View full text Add to dashboard Cite

The liver is a key node of whole-body nutrient and fuel metabolism and is also the principal site for detoxification of xenobiotic compounds. As such, hepatic metabolite concentrations and/or turnover rates inform on the status of both hepatic and systemic metabolic diseases as well as the disposition of medications. As a tool to better understand liver metabolism in these settings, in vivo magnetic resonance spectroscopy (MRS) offers a non-invasive means of monitoring hepatic metabolic activity in real time both by direct observation of concentrations and dynamics of specific metabolites as well as by observation of their enrichment by stable isotope tracers. This review summarizes the applications and advances in human liver metabolic studies by in vivo MRS over the past 35 years and discusses future directions and opportunities that will be opened by the development of ultra-high field MR systems and by hyperpolarized stable isotope tracers.

show abstract

Monounsaturated fat rapidly induces hepatic gluconeogenesis and whole-body insulin resistance

Cited by 24 publications

References 40 publications

FGF21 defines a potential cardio-hepatic signaling circuit in human heart failure

FGF21 defines a potential cardio-hepatic signaling circuit in human heart failure

Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle

Non-Invasive Analysis of Human Liver Metabolism by Magnetic Resonance Spectroscopy

Contact Info

Product

Resources

About