A protein kinase C α and β inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes (original) (raw)
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2020
Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKCα and PKCβ, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKCα and PKCβ in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by bl...
MedComm, 2021
Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/ MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque
Adipocyte, 2012
PKCl, an atypical member of the multifunctional protein kinase C family, has been implicated in the regulation of insulinstimulated glucose transport and of the intracellular immune response. To further elucidate the role of this cellular regulator in diet-induced obesity and insulin resistance, we generated both liver (PKC-Alb) and adipose tissue (PKC-Ap2) specific knockout mice. Body weight, fat mass, food intake, glucose homeostasis and energy expenditure were evaluated in mice maintained on either chow or high fat diet (HFD). Ablation of PKCl from the adipose tissue resulted in mice that were indistinguishable from their wild-type littermates. However, PKC-Alb mice were resistant to diet-induced obesity (DIO). Surprisingly this DIO resistance was not associated with either a reduction in caloric intake or an increase in energy expenditure as compared with their wild-type littermates. Furthermore, these mice displayed an improvement in glucose tolerance. When maintained on chow diet, these mice were similar to wild types in respect to body weight and fat mass, yet insulin sensitivity was impaired compared with wt littermates. Taken together these data suggest that hepatic PKCl is modulating insulin-mediated glucose turnover and response to high fat diet feeding, thus offering a deeper understanding of an important target for anti-obesity therapeutics.
Diabetes, 2003
In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms and are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKC/ or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKC/ and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulinstimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40 -50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKC/ activity ϳ2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKC/ protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKC/. Importantly, weight loss in obese subjects normalizes PKC/ activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulinstimulated PKC/ activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects. . GDR, glucose disposal rate; IRS, insulin receptor substrate; OGTT, oral glucose tolerance test; PDK-1, phosphoinositide-dependent protein kinase-1; PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; VLCD, very-low-calorie diet.
Metabolism, 2012
Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small-molecule PKC-ι/λ inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-λ, in which partial deficiency of muscle PKC-λ impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H- -(1a,2b,3b,4a)], binds to the substrate-binding site of PKC-λ/ι, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PB1-binding domains of aPKC-λ/ι/ζ and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKCdependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-ι in M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 1 ( 2 0 1 2 ) 4 5 9 -4 6 9 MP Sajan oversaw conduct of all laboratory studies, supervised laboratory personnel, performed assays, and collected and analyzed data. S Nimal conducted laboratory assays. S Mastorides provided resources for measuring clinical parameters. M Acevedo-Duncan provided ICAPP. AL Fields provided ATM. CR Kahn and M Leitges provided original MCK-Cre transgenic and PKC-λ floxed mice, respectively, used for generation of the mouse colony. RV Farese provided overall planning and direction of the studies, analyzed data, and wrote the paper. A v a i l a b l e o n l i n e a t w w w . s c i e n c e d i r e c t . c o m Metabolism w w w . m e t a b o l i s m j o u r n a l . c o m
2010
Among the multitude of dysregulated signalling mechanisms that comprise insulin resistance in divergent organs, the primary events in the development of type 2 diabetes are not well established. As protein kinase C (PKC) activation is consistently present in skeletal muscle of obese and insulin resistant subjects, we generated a transgenic mouse model that overexpresses constitutively active PKC-2 in skeletal muscle to test whether activation of PKC is sufficient to cause an aversive whole-body phenotype. Upon this genetic modification, increased serine phosphorylation in Irs1 was observed and followed by impaired 3 H-deoxy-glucose uptake and muscle glycogen content, and transgenic mice exhibited insulin and glucose intolerance as they age. Muscle histochemistry revealed an increase in lipid deposition (intramyocellular lipids), and transgenic mice displayed impaired expression of transcriptional regulators of genes involved in fatty acid oxidation (peroxisome proliferator-activated receptor-␦, PGC-1, acyl-CoA oxidase) and lipolysis (hormone-sensitive lipase). In this regard, muscle of transgenic mice exhibited a reduced capacity to oxidize palmitate and contained less mitochondria as determined by citrate synthase activity. Moreover, the phenotype included a profound decrease in the daily running distance, intraabdominal and hepatic fat accumulation and impaired insulin action in the brain. Together, our data suggest that activation of a classical PKC in skeletal muscle as present in the pre-diabetic state is sufficient to cause disturbances in whole-body glucose and lipid metabolism followed by profound alterations in oxidative capacity, ectopic fat deposition and physical activity.
AJP: Endocrinology and Metabolism, 2006
In this study, we investigated the metabolic phenotype of protein kinase C theta (PKC ) knockout mice (C57BL/6J) on chow diet and high fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On chow diet, body weight and food intake were not changed in the KO mice, however body fat content was increased with corresponding decrease in body lean mass. Energy expenditure and spontaneous physical activity were decreased in the KO mice. On HFD, energy expenditure and physical activity remained low in the KO mice. The body weight and fat content were increased rapidly in the KO mice. At eight weeks on HFD, severe insulin resistance was detected in the KO mice with hyperinsulinemic-euglycemic clamp and insulin tolerance test. Insulin action in both hepatic and peripheral tissues was reduced in the KO mice. Plamsa FFA was increased and expression of adiponectin in the adipose tissue was decreased in the KO mice on HFD. This study suggests that loss of PKC reduces energy expenditure, and increases the risk of dietary obesity and insulin resistance in mice.