TY  - JOUR
A1  - Mayer, Alexander E.
A1  - Löffler, Mona C.
A1  - Loza Valdés, Angel E.
A1  - Schmitz, Werner
A1  - El-Merahbi, Rabih
A1  - Trujillo-Viera, Jonathan
A1  - Erk, Manuela
A1  - Zhang, Thianzhou
A1  - Braun, Ursula
A1  - Heikenwalder, Mathias
A1  - Leitges, Michael
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling
JF  - Science Signaling
N2  - Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.
KW  - Protein kinase D3 (PKD3)
KW  - cholesterol
KW  - diacylglycerol (DAG)
KW  - liver
KW  - metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025
ET  - accepted manuscript
ER  - 
TY  - JOUR
A1  - Viera, Jonathan Trujillo
A1  - El-Merahbi, Rabih
A1  - Nieswandt, Bernhard
A1  - Stegner, David
A1  - Sumara, Grzegorz
T1  - Phospholipases D1 and D2 Suppress Appetite and Protect against Overweight
JF  - PLoS ONE
N2  - Obesity is a major risk factor predisposing to the development of peripheral insulin resistance and type 2 diabetes (T2D). Elevated food intake and/or decreased energy expenditure promotes body weight gain and acquisition of adipose tissue. Number of studies implicated phospholipase D (PLD) enzymes and their product, phosphatidic acid (PA), in regulation of signaling cascades controlling energy intake, energy dissipation and metabolic homeostasis. However, the impact of PLD enzymes on regulation of metabolism has not been directly determined so far. In this study we utilized mice deficient for two major PLD isoforms, PLD1 and PLD2, to assess the impact of these enzymes on regulation of metabolic homeostasis. We showed that mice lacking PLD1 or PLD2 consume more food than corresponding control animals. Moreover, mice deficient for PLD2, but not PLD1, present reduced energy expenditure. In addition, deletion of either of the PLD enzymes resulted in development of elevated body weight and increased adipose tissue content in aged animals. Consistent with the fact that elevated content of adipose tissue predisposes to the development of hyperlipidemia and insulin resistance, characteristic for the pre-diabetic state, we observed that Pld1\(^{-/-}\) and Pld2\(^{-/-}\) mice present elevated free fatty acids (FFA) levels and are insulin as well as glucose intolerant. In conclusion, our data suggest that deficiency of PLD1 or PLD2 activity promotes development of overweight and diabetes.
KW  - enzyme regulation
KW  - insulin resistance
KW  - body weight
KW  - mouse models
KW  - bioenergetics
KW  - insulin
KW  - hypothalamus
KW  - adipose tissue
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179729
VL  - 11
IS  - 6
ER  -