title: PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans.
abstract: C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.
authors.affiliation: Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bezy
authors.forename: Thien T
authors.initials: TT
authors.lastname: Tran
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Brice
authors.initials: B
authors.lastname: Emanuelli
authors.forename: Jonathan
authors.initials: J
authors.lastname: Winnay
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.forename: Joel
authors.initials: J
authors.lastname: Haas
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Biddinger
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Patti
authors.forename: George L
authors.initials: GL
authors.lastname: King
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D004041:Dietary Fats / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D018149:Glucose Intolerance / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology / Q000517:prevention & control; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000201:enzymology*; D051745:Protein Kinase C-delta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D014280:Triglycerides; D051745:Protein Kinase C-delta