Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria

Mishra, Akansha; Liu, Siming; Promes, Joseph A.; Harata, Mikako; Sivitz, William I.; Fink, Brian D.; Bhardwaj, Gourav; O’Neill, Brian T.; Chen, Kang; Sah, Rajan; Strack, Stefan; Stephens, Samuel B.; King, Timothy H.; Jackson, Laura; Greenberg, Andrew S.; Anokye‐Danso, Frederick; Ahima, Rexford S.; Ankrum, James A.; Imai, Yumi

doi:10.1172/jci.insight.144341

Cited by 13 publications

(11 citation statements)

References 59 publications

(128 reference statements)

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“…These results are not consistent with those of earlier work in rodents ( 24 , 37 ), yet they are with recent findings in rat INS-1 β-cells and human islets ( 41 ). Although this newer work had only limited molecular detail in how compromising LD formation negatively impacted β-cell function, their physiological results showed that mitochondrial health and activity were negatively impacted in both rodent β-cells and human islets ( 41 ). Notably, our RNA-seq data also suggest that the integrity of PLIN2KD mitochondria is compromised ( Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 99%

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

Tong

Stein

2021

Diabetes

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Supplemental Figures and Legends Supplemental Figure 1. PLIN2KD significantly altered TGFβ/SMAD pathway genes. (A) Heat maps showing significantly elevated levels of TGFβ/SMAD pathway-related genes in PLIN2KD EndoCβH2-Cre β cells. The color keys represent the row-wise Z-score. (B) Notably, GDF15 level appears to be PLIN2 dependent (directly extracted from bulk RNA-seq data), TPM: Transcripts Per Million. All error bars indicate SD, n=3, * P<0.05 vs Sham. Supplemental Figure 2. NAC cannot rescue EA induced effectors of ER stress. EndoCβH2-Cre cells (termed Sham) were treated with EA (500 µM, 24h) in the presence of absence of N-acetyl cysteine (NAC, 1mM). The expression of stress induced IRE1α and XBP-1 ratio (i.e., spliced/total) mRNA levels were analyzed by qPCR. All error bars indicate SD, n=3, * P<0.05, ** P<0.01, *** P<0.05 vs Sham Supplemental Figure 3. EA provoked a stronger stress gene response than PA. Sham cells were treated with PA (500 µM, 48 hours) or EA (500 µM, 24 hours) and then analyzed by qRT-PCR for FEV, IRE1α and XBP-1 ratio (i.e., spliced/total). All of these PLIN2KD and ER stress markers were more highly elevated in EA cells. All error bars indicate SD, n=3, * P<0.05, ** P<0.01, *** P<0.05 vs Sham. Supplemental Figure 4. PLIN2 manipulation induced many changes in the expression of gene important to mitochondria function and health. Heat maps showing changes in many different mitochondrial genes in PLIN2KD and PLIN2OE cells, including (A) electron transport chain and mitochondrial encoding, (B) fusion and fission, (C) ion balance and (D) mitophagy. The color keys represent the row-wise Z-score.

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Section: Discussioncontrasting

confidence: 99%

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

Tong

Stein

2021

Diabetes

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“…An additional class of proteins that had an increased interaction with spinophilin was the perilipins, which protect the beta cell from another form of stress in T2D known as lipotoxicity (37). Perlipin-2 has previously been shown to regulate insulin secretion (38); however, the function of perilipin-1 and 4 detected here are less well-known. Future perifusion studies of islets from spinophilin knock out mice (global or cell type-specific) will be required to completely delineate spinophilin's potential role in regulating phasic insulin secretion.…”

Section: Discussionmentioning

confidence: 73%

Mechanisms of spinophilin-dependent pancreas dysregulation underlying diabesity

Stickel

Mosley

Doud

et al. 2023

Preprint

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Objective: Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. While spinophilin is enriched in neurons, its roles in non-neuronal tissues, such as beta cells of the pancreatic islets, are unclear. Methods & Results: We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. Using proteomics and immunoblotting-based approaches we identified multiple putative spinophilin interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high fat-fed (HFF) models of obesity. Moreover, loss of spinophilin specifically in pancreatic beta cells improved glucose tolerance without impacting body weight. Conclusion: Our data further support a role for spinophilin in mediating pathophysiological changes in body weight and whole-body metabolism associated with obesity and provide the first evidence that spinophilin mediates obesity-dependent pancreatic dysfunction that leads to deficits in glucose homeostasis or diabesity.

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“…Downregulation of perilipin 2 (PLIN2), which is a key scaffold protein and resides on the surface of LDs, ameliorates the effects of fatty acid-and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them (38). Contrary to that report, the other studies showed that downregulation of PLIN2 reduced the levels of FFAs incorporated into LD and resulted in mitochondrial dysfunction (39) and endoplasmic reticulum (ER) stress (40), as LD formation protects cells against toxic effects of FFA (41). In any case, excess LD accumulation may reflect inappropriate lipid metabolism beyond FFA homeostasis, which causes lipotoxicity-induced endoplasmic reticulum stress, resulting in impaired insulin granule maturation and decreased insulin secretory capacity (42,43).…”

Section: Discussionmentioning

confidence: 81%

Lipid droplet accumulation in β cells in patients with type 2 diabetes is associated with insulin resistance, hyperglycemia and β cell dysfunction involving decreased insulin granules

et al. 2022

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Background and objectivePancreatic fat is a form of ectopic fat. Lipid droplets (LDs) are also observed in β cells; however, the pathophysiological significance, especially for β cell function, has not been elucidated. Our aim was to assess LD accumulation in β cells in various stages of glucose intolerance and to clarify its relationship with clinical and histological parameters.MethodsWe examined 42 Japanese patients who underwent pancreatectomy. The BODIPY493/503-positive (BODIPY-positive) area in β cells was measured in pancreatic sections from 32 patients. The insulin granule numbers were counted in an additional 10 patients using electron microscopy.ResultsThe BODIPY-positive area in β cells in preexisting type 2 diabetes patients was higher than that in normal glucose tolerance patients (p = 0.031). The BODIPY-positive area in β cells was positively correlated with age (r = 0.45, p = 0.0097), HbA1c (r = 0.38, p = 0.0302), fasting plasma glucose (r = 0.37, p = 0.045), and homeostasis model assessment insulin resistance (r = 0.41, p = 0.049) and negatively correlated with an increase in the C-peptide immunoreactivity level by the glucagon test (r = -0.59, p = 0.018). The ratio of mature insulin granule number to total insulin granule number was reduced in the patients with rich LD accumulation in β cells (p = 0.039).ConclusionsType 2 diabetes patients had high LD accumulation in β cells, which was associated with insulin resistance, hyperglycemia, aging and β cell dysfunction involving decreased mature insulin granules.

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Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria

Cited by 13 publications

References 59 publications

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

Mechanisms of spinophilin-dependent pancreas dysregulation underlying diabesity

Lipid droplet accumulation in β cells in patients with type 2 diabetes is associated with insulin resistance, hyperglycemia and β cell dysfunction involving decreased insulin granules

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