4-Hydroxyisoleucine ameliorates an insulin resistant-like state in 3T3-L1 adipocytes by regulating TACE/TIMP3 expression

Abstract

BackgroundObesity-associated insulin resistance (IR) is highly correlated with soluble tumor necrosis factor-α (sTNF-α), which is released from transmembranous TNF-α by TNF-α converting enzyme (TACE). In vivo, TACE activity is suppressed by tissue inhibitor of metalloproteinase 3 (TIMP3). Agents that can interact with TACE/TIMP3 to improve obesity-related IR would be highly valuable. In the current study, we assessed whether (2S,3R,4S)-4-hydroxyisoleucine (4-HIL) could modulate TACE/TIMP3 and ameliorate an obesity-induced IR-like state in 3T3-L1 adipocytes.Materials and methods3T3-L1 adipocytes were incubated in the presence of 25 mM glucose and 0.6 nM insulin to induce an IR-like state, and were then treated with different concentrations of 4-HIL or 10 µM pioglitazone (positive control). The glucose uptake rate was determined using the 2-deoxy-[3H]-d-glucose method, and the levels of sTNF-α in the cell supernatant were determined using ELISA. The protein expression of TACE, TIMP3, and insulin signaling-related molecules was measured using western blotting.ResultsExposure to high glucose and insulin for 18 hours increased the levels of sTNF-α in the cell supernatant. The phosphorylation of insulin receptor substrate-1 (IRS-1) Ser307 and Akt Ser473 was increased, whereas the protein expression of IRS-1, Akt, and glucose transporter-4 was decreased. The insulin-induced glucose uptake was reduced by 67% in 3T3-L1 adipocytes, which indicated the presence of an IR-like state. The above indexes, which demonstrated the successful induction of an IR-like state, were reversed by 4-HIL in a dose-dependent manner by downregulating and upregulating the protein expression of TACE and TIMP3 proteins, respectively.Conclusion4-HIL improved an obesity-associated IR-like state in 3T3-L1 adipocytes by targeting TACE/TIMP3 and the insulin signaling pathway.

Nutritional and therapeutic properties of fenugreek (Trigonella foenum-graecum): a review

“…The studies also provide the information about the pathway of signal transduction and upgraded the insulin confrontation, which is induced by obesity in adipocytes (3T3-L1). [48] Alike findings have been described in Zucker rats, which were obese given the seeds of fenugreek. Researcher experiments the livers of the rats which were obese, the decrease in tumour necrosis factor intensities, important rise in receptors of membrane and TNF receptor 2.…”

Orientin Protects Podocytes from High Glucose Induced Apoptosis through Mitophagy

“…Trigonella foenum‐graecum (fenugreek) seed is a well‐known traditional medicinal herb and possesses antidiabetic, hepatoprotective, antihyperlipidemic, antiobesity, anticancer, anti‐inflammatory, antioxidant, and miscellaneous pharmacological effects. Orientin, one of the isolable bioactive compounds of Fenugreek, is often used in various bioactivity studies due to its extensive beneficial properties, such as antioxidant, anti‐inflammation, cardioprotective, neuroprotective, antidepressant‐like, anti‐adipogenesis, and antinociceptive effects .…”

Fenugreek (Trigonella Foenum-Graecum) Seed Flour and Diosgenin Preserve Endothelium-Dependent Arterial Relaxation in a Rat Model of Early-Stage Metabolic Syndrome

“…The underlying mechanism encompass enhancement of glucose uptake by translocation of GLUT4 (glucose transporter 4) to the plasma membrane [ 56 ]. Moreover, 4-OH-Ile also exerts anti-inflammatory action via reducing TNF-α mRNA expression [ 57 , 58 ]. Galactomannan, another component of fenugreek, inhibits some lipid- and carbohydrate-hydrolyzing enzymes, such as α-glucosidase, that leads to decreased lipid and glucose absorption [ 59 , 60 , 61 ].…”