Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca2+ release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.

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Effects of PYY3–36 and GLP-1 on energy intake, energy expenditure, and appetite in overweight men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00569.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. E1248-E1256 ◽

Cited By ~ 69

Author(s):

Julie Berg Schmidt ◽

Nikolaj Ture Gregersen ◽

Sue D. Pedersen ◽

Johanne L. Arentoft ◽

Christian Ritz ◽

...

Keyword(s):

Energy Expenditure ◽

Synergistic Effect ◽

Energy Intake ◽

Fat Metabolism ◽

Vital Signs ◽

Healthy Male ◽

Double Blinded ◽

Male Subjects ◽

Infusion Period ◽

Blood Variables

Our aim was to examine the effects of GLP-1 and PYY3–36, separately and in combination, on energy intake, energy expenditure, appetite sensations, glucose and fat metabolism, ghrelin, and vital signs in healthy overweight men. Twenty-five healthy male subjects participated in this randomized, double-blinded, placebo-controlled, four-arm crossover study (BMI 29 ± 3 kg/m2, age 33 ± 9 yr). On separate days they received a 150-min intravenous infusion of 1) 0.8 pmol·kg−1·min−1 PYY3–36, 2) 1.0 pmol·kg−1·min−1 GLP-1, 3) GLP-1 + PYY3–36, or 4) placebo. Ad libitum energy intake was assessed during the final 30 min. Measurements of appetite sensations, energy expenditure and fat oxidation, vital signs, and blood variables were collected throughout the infusion period. No effect on energy intake was found after monoinfusions of PYY3–36 (−4.2 ± 4.8%, P = 0.8) or GLP-1 (−3.0 ± 4.5%, P = 0.9). However, the coinfusion reduced energy intake compared with placebo (−30.4 ± 6.5%, P < 0.0001) and more than the sum of the monoinfusions ( P < 0.001), demonstrating a synergistic effect. Coinfusion slightly increased sensation of nausea ( P < 0.05), but this effect could not explain the effect on energy intake. A decrease in plasma ghrelin was found after all treatments compared with placebo (all P < 0.05); however, infusions of GLP-1 + PYY3–36 resulted in an additional decrease compared with the monoinfusions (both P < 0.01). We conclude that coinfusion of GLP-1 and PYY3–36 exerted a synergistic effect on energy intake. The satiating effect of the meal was enhanced by GLP-1 and PYY3–36 in combination compared with placebo. Coinfusion was accompanied by slightly increased nausea and a decrease in plasma ghrelin, but neither of these factors could explain the reduction in energy intake.

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Involvement of PRIP, Phospholipase C-related, but Catalytically Inactive Protein, in Bone Formation

Journal of Biological Chemistry ◽

10.1074/jbc.m111.235903 ◽

2011 ◽

Vol 286 (35) ◽

pp. 31032-31042 ◽

Cited By ~ 8

Author(s):

Koshiro Tsutsumi ◽

Miho Matsuda ◽

Miho Kotani ◽

Akiko Mizokami ◽

Ayako Murakami ◽

...

Keyword(s):

Bone Formation ◽

Phospholipase C ◽

Inactive Protein

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Abstract 1918 P122 Protein, a Positive Regulator for Phospholipase C-σ1, Is Upregulated and Involved in Enhanced Calcium Signaling in Human Coronary Spasm

Circulation ◽

10.1161/circ.118.suppl_18.s_405 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Reiichi Murakami ◽

Tomohiro Osanai ◽

Hirofumi Tomita ◽

Ken Okumura

Keyword(s):

Protein Expression ◽

Phospholipase C ◽

Protein A ◽

Coronary Spasm ◽

Amino Acid Replacement ◽

Hek293 Cells ◽

Gene Expressions ◽

Human Embryonic Kidney Cells ◽

Control Subjects ◽

Intracellular Ca

We previously showed that the activity of phospholipase C (PLC)-σ1, a key enzyme for Ca 2+ signaling in the coronary artery smooth muscle, was enhanced threefold in patients with coronary spastic angina (CSA) compared with control subjects. Structural mutation of PLC-σ1 (864G-A) variant with the amino acid replacement of arginine 257 by histidine is one mechanism for the enhanced PLC-σ1 activity, but this was observed in only 10% of CSA patients. PLC-σ1 was shown to be positively regulated by p122 protein. We examined the possible role of p122 protein in the mechanism for enhanced PLC-σ1 activity. In 11 patients with CSA and 9 control subjects without CSA, skin fibroblasts were obtained at the coronary angiography and were cultured. Protein and gene expressions of p122 were determined by Western blot analysis and real-time quantitative RT-PCR, respectively. The protein expression of p122 was enhanced in CSA threefold compared with control subjects (237±17 vs 85±13 units, p<0.0001). The gene expression of p122 was also enhanced in CSA by 36.1±8.7% compared with control (p<0.01). We further examined whether the upregulated p122 protein is associated with the enhancement of intracellular Ca 2+ signaling. Human embryonic kidney cells (HEK293) were cultured and transfected by muscarine M1 receptor. In the cells expressing normal PLC-σ1, acethylcholine (ACh) at 10 −6 and 10 −5 mol/L caused a dose-dependent, rapid transient increase in [Ca 2+ ] i followed by a lower but sustained phase of the increase. We further transfected the HEK293 cells by p122, which resulted in the increased expression of p122 protein two-to threefold. [Ca 2+ ] i at baseline was 23±1 nmol/L in the cells without p122 transfection and 39±2 nmol/L in those with p122 (P<0.01). The peak increase in [Ca 2+ ] i from the baseline after ACh was significantly greater in the cells transfected with p122 than in those without transfection (68±6 versus 33±4 nmol/L at 10 −6 mol/L Ach, and 128±11 versus 67±8 nmol/L at 10 −5 mol/L ACh, both P<0.01). The sustained phase of [Ca 2+ ] i increase was prolonged in the cells with p122 transfection compared with those without transfection. In conclusion, the enhanced p122 protein expression is involved in the pathogenesis of CSA by enhancing intracellular Ca 2+ signaling.

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Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

10.2337/figshare.13652960 ◽

2021 ◽

Author(s):

Ada Admin ◽

David M Presby ◽

Michael C Rudolph ◽

Vanessa D Sherk ◽

Matthew R Jackman ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Energy Expenditure ◽

Lipoprotein Lipase ◽

Weight Regain ◽

Energy Homeostasis ◽

Fat Metabolism ◽

Fat Oxidation ◽

Oxidative Capacity ◽

Expression Of Genes

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism genes were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.

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