Photobiomodulation therapy decreases free fatty acid generation and release in adipocytes to ameliorate insulin resistance in type 2 diabetes

doi:10.1016/j.cellsig.2019.109491

Cellular Signalling

Volume 67, March 2020, 109491

https://doi.org/10.1016/j.cellsig.2019.109491 Get rights and content

Highlights

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PBMT decreases FFA generation and release in insulin-resistant adipose cells and tissues;
•
PBMT promotes ROS generation and activates PTEN/AKT signaling.
•
Photoactivation of AKT inhibits FoxO1 transcriptional activity and lipolysis.
•
PBMT ameliorates insulin resistance in adipocytes and diabetic mice.

Abstract

Excessive circulating free fatty acids (FFA) cause insulin resistance in peripheral tissues by inhibiting the proximal insulin signaling pathway. White adipose tissue (WAT) is a primary source of FFA generation and release through triglyceride (TG) hydrolysis. Thus, reducing excessive lipolysis in adipocytes ameliorates whole-body insulin resistance in type 2 diabetes. Here, we found that a noninvasive photobiomodulation therapy (PBMT), decreased FFA generation and release in WATs from high-fat diet (HFD)-fed mice and diabetic db/db mice. Meanwhile, plasma FFA and TG levels were reduced in two mouse models after PBMT. PBMT promoted mitochondrial reactive oxygen species (ROS) generation, which inhibited phosphatase and tensin homologue (PTEN) and promoted protein kinase B (AKT) activation. Photoactivation of AKT inhibited the transcriptional activity of Forkhead box transcription factor O1 (FoxO1), reducing expression of lipolytic enzymes and FFA generation and release. Eliminating ROS elimination or inhibiting AKT blocked the effects of the laser therapy in vivo and in vitro. Taken together, PBMT suppresses FFA generation and release in insulin-resistant adipocytes, contributing to improvement of insulin resistance in mouse models of type 2 diabetes.

Graphical abstract

Introduction

Type 2 diabetes and obesity are characterized by insulin resistance, which presents with reduced insulin sensitivity in peripheral tissues. Free fatty acids (FFA) are key factors responsible for insulin resistance [1]. FFA, adipocyte-derived secreted products formed through triglyceride (TG) hydrolysis, are a primary energy source during fasting [2]. However, elevated plasma FFA levels can cause severe whole-body insulin resistance [1,2], suppressing muscle glucose uptake and glycogen synthesis [3], elevating hepatic gluconeogenesis [4] and adipose lipolysis [5], and causing β-cell dysfunction [6]. Reducing lipolysis and plasma FFA levels ameliorates whole-body insulin resistance in type 2 diabetes [7,8]. Our previous study found that photobiomodulation therapy (PBMT) decreased FFA generation and release in dexamethasone-induced insulin-resistant 3T3-L1 adipocytes [9]. However, it is unclear how PBMT inhibits lipolysis in adipose tissues and whether PBMT improves insulin sensitivity in type 2 diabetes.

PBMT using the visible and near-infrared light has gained attention as a nondestructive and non-damaging physical therapy in ophthalmology, neurology, dermatology, dentology, and regenerative medicine [10,11]. Recent evidence suggests that PBMT promotes the formation of tertiary dentin [12], accelerates platelet biogenesis to treat thrombocytopenia [13], and ameliorates amyloid beta (Aβ)-induced neurons damage [14,15]. Therefore, PBMT has great potential in translational medicine. PBMT-promoted reactive oxygen species (ROS) production has been observed in several cells [12,16,17]. ROS oxidatively inhibits phosphatase and tensin homologue (PTEN), which dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) and negatively regulates AKT signaling, through formation of a disulfide bond between the active site Cys124 and Cys71 [18,19]. Activation of insulin-stimulated AKT signaling promotes lipid storage and suppresses FFA production and release in white adipose tissue (WAT) [20]. Together, these findings led us to hypothesize that PBMT might decrease plasma FFA levels and improve insulin resistance by inhibiting adipose lipolysis in type 2 diabetes. In the present study, we investigated the effects and mechanisms of PBMT on lipid metabolism in type 2 diabetes. We found that PBMT ameliorated insulin resistance by reducing adipose FFA release, suggesting a novel therapeutic strategy for type 2 diabetes.

Section snippets

Animals

Male C57BLKS/J-lepr^db/lepr^db diabetic (db/db) mice were obtained from Model Animal Research Center of Nanjing University, Nanjing, China. Male C57BL/6J mice were obtained from Beijing Huafukang Bioscience Co. Inc., Beijing, China. For high-fat diet (HFD)-fed mice, 5-week-old C57BL/6J mice were fed an HFD (60%; D12492, Beijing Huafukang Bioscience Co. Inc.).

Animals studies were performed in accordance with the guidelines of The Care and Use of Laboratory Animals (Institute of Laboratory Animal

PBMT decreases FFA generation and release in adipose cells and tissues

To demonstrate that PBMT reduced FFA release in insulin-resistant adipocytes, we established an insulin resistance model of 3T3-L1 adipocytes (Fig. S1A single bond C). FFA release from IR-3T3-L1 adipocytes after PBMT was significantly decreased in a laser dose and time-dependent manner (Figs. 1A and S1D). A most decrease was observed at 12 h after the dose of 8 J/cm² (635 nm, 26.7 mW/cm², 5 min), which was selected for subsequent studies (Figs. 1A and S1D). Intracellular FFA and glycerol levels were

Discussion

WAT plays important roles in modulating glucose-lipid metabolic homeostasis. Although adipose tissues account for only a fraction of glucose disposal (5–20%), abnormal lipid metabolism in adipose tissues has profound implications for glucose homeostasis and whole-body insulin resistance [31]. In type 2 diabetes, excessive lipolysis in adipocytes elevates plasma FFA concentrations [32]. High circulating FFA levels cause muscle insulin resistance by inhibiting the proximal insulin signaling

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

We gratefully acknowledge Dr. Georges Bismuth (Université René Descartes, and Laboratoire Labellisé par la Ligue Nationale contre le Cancer) for kindly providing plasmids. This work was supported by the National Natural Science Foundation of China (61361160414; 31470072), the Natural Science Foundation of Guangdong Province, China (2014A030313419), and the Science and Technology Planning Project of Guangdong Province (Guangdong-Hong Kong Joint Innovation Project), China (2014B050504009).

Author contributions

D.X. and L.G. designed the research; L.G., S.G., and L.H. performed the experiments; L.G. and S.G. processed and analyzed the experiment data and results; D.X. and L.G. supervised the project; L.G. and Z.Z. wrote the manuscript.

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Photobiomodulation therapy decreases free fatty acid generation and release in adipocytes to ameliorate insulin resistance in type 2 diabetes

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Animals

PBMT decreases FFA generation and release in adipose cells and tissues

Discussion

Declaration of competing interest

Acknowledgements

Author contributions

Prog. Mol. Biol. Transl. Sci.

Metab. Clin. Exp.

J. Biol. Chem.

Cell. Signal.

J. Biol. Chem.

Cell Metab.

Free Radic. Biol. Med.

Kidney Int.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Prog. Lipid Res.

J. Biol. Chem.

Cell

J. Biol. Chem.

Best Pract. Res. Clin. Endocrinol. Metab.

Mechanism of free fatty acid-induced insulin resistance in humans

J. Clin. Invest.

Adipocytes as regulators of energy balance and glucose homeostasis

Nature

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

Nat. Rev. Mol. Cell Biol.

Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction

Eur. J. Clin. Investig.

Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects

Diabetes

Intracellular signaling cascades following light irradiation

Laser Photonics Rev.

Light-emitting diode therapy and low-level light therapy are photobiomodulation therapy

Photobiomod. Photomed. Laser Surg.