Publications (58) View all
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Article: Thyroid hormone receptor β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways.
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ABSTRACT: Liver specific thyroid hormone receptor β (TRβ) specific agonists are potent lipid lowering drugs that also hold promise for treating nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat fed male Sprague Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ and liver specific thyromimetic, also prevented hepatic steatosis, but did not induce fasting hyperglycemia, increase basal EGP rate or diminish hepatic insulin sensitivity. Surprisingly, insulin stimulated peripheral glucose disposal was diminished due to a decrease in insulin stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB2115 treatment was associated with a decrease in GLUT4 protein content. Thus, though both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.AJP Endocrinology and Metabolism 05/2013; · 4.75 Impact Factor -
Article: CREB-regulated transcription coactivator 2 (CRTC2) promotes glucagon clearance and hepatic amino acid catabolism to regulate glucose homeostasis.
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ABSTRACT: CREB-regulated transcription coactivator 2 (CRTC2) regulates transcription of gluconeogenic genes by specifying targets for the transcription factor cAMP-responsive element binding protein (CREB) in response to glucagon. We used an antisense oligonucleotide (ASO) directed against CRTC2 in both normal rodents and in rodent models of increased gluconeogenesis to better understand the role of CRTC2 in metabolic disease. As expected, in the context of severe hyperglycemia and elevated hepatic glucose production (HGP), CTRC2 knockdown (KD) improved glucose homeostasis by reducing endogenous glucose production. Interestingly, despite the known role of CRTC2 in coordinating gluconeogenic gene expression, CRTC2 KD in a rodent model of type 2 diabetes (T2D) resulted in surprisingly little alteration of glucose production. However, CRTC2 KD animals had elevated circulating concentrations of glucagon, and a ~90% reduction in glucagon clearance. When this phenomenon was prevented with somatostatin or a glucagon-neutralizing antibody, endogenous glucose production was reduced with CRTC2 KD. Additionally, CRTC2 inhibition resulted in reduced expression of several glucagon-induced pyridoxal-5'-phosphate-dependent enzymes that convert amino acids to gluconeogenic intermediates, suggesting that it may control substrate availability as well as gluconeogenic gene expression. Conclusions: CRTC2 is an important regulator of gluconeogenesis with tremendous impact in models of elevated hepatic glucose production. Surprisingly, it is also part of previous unidentified negative feedback loop that degrades glucagon and regulates amino acid metabolism to coordinately control glucose homeostasis in vivo.Journal of Biological Chemistry 04/2013; · 4.77 Impact Factor -
Article: Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance.
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ABSTRACT: We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsies, and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high-fat-fed (HFF) rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in ZDF rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance and type 2 diabetes.Diabetes 02/2013; · 8.29 Impact Factor -
Article: Fasting hyperglycemia in the Goto-Kakizaki rat is dependent on corticosterone: a confounding variable in rodent models of type 2 diabetes.
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ABSTRACT: The Goto-Kakizaki (GK) rat is an inbred model of type 2 diabetes (T2D); GK rats are lean but have hyperglycemia and increased gluconeogenesis. However, fasting hyperglycemia in other commonly used rodent models of T2D is associated with increased corticosterone, and thus the underlying mechanism for hyperglycemia differs significantly from T2D in humans. Information regarding corticosterone in the GK rat is not readily available. We studied 14- to 16-week-old GK rats in comparison with age-matched control Wistar-Kyoto (WK) rats. GK rats had lower body weights (WK: 343±10 g vs GK: 286±9 g, P<0.01), but higher plasma glucose concentrations (WK: 132±1.5 mg/dl vs GK: 210±11.7 mg/dl, P<0.01). This was associated with an ∼twofold increase in PEPCK1 expression (P<0.05). However, these findings were also associated with elevations in plasma corticosterone and urinary corticosterone excretion. Ketoconazole (KTZ) treatment in GK rats reduced plasma corticosterone, fasting glucose (GK: 218±15 mg/dl vs GK-KTZ: 135±19 mg/dl, P<0.01) and rates of glucose production [GK: 16.5±0.6 mg/(kg-minute) vs GK-KTZ: 12.2±0.9 mg/(kg-minute), P<0.01]. This was associated with an ∼40% reduction in hepatic PEPCK1 expression as well as a 20% reduction in alanine turnover. Thus, hypercorticosteronemia might contribute to the diabetic phenotype of GK rats and should be considered as a potential confounder in rodent models of T2D.Disease Models and Mechanisms 08/2012; 5(5):681-5. · 4.94 Impact Factor -
Article: Mechanisms for insulin resistance: common threads and missing links.
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ABSTRACT: Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance.Cell 03/2012; 148(5):852-71. · 32.40 Impact Factor
