Insulin receptor substrate‐1 inhibits high‐fat diet‐induced obesity by browning of white adipose tissue through miR‐503

Vasohibin-1 (Vash1), originally isolated as an endothelium-derived angiogenesis inhibitor, has a characteristic of promoting stress tolerance in endothelial cells (ECs). We therefore speculated that the lack of the vash1 gene would result in a short lifespan. However, to our surprise, vash1−/− mice lived significantly longer with a milder senescence phenotype than wild-type (WT) mice. We sought the cause of this healthy longevity and found that vash1−/− mice exhibited mild insulin resistance along with reduced expression of the insulin receptor (insr), insulin receptor substrate 1 (irs-1), and insulin receptor substrate 2 (irs-2) in their white adipose tissue (WAT) but not in their liver or skeletal muscle. The expression of vash1 dominated in the WAT among those 3 organs. Importantly, vash1−/− mice did not develop diabetes even when fed a high-fat diet. These results indicate that the expression of vash1 was required for the normal insulin sensitivity of the WAT and that the target molecules for this activity were insr, irs1, and irs2. The lack of vash1 caused mild insulin resistance without the outbreak of overt diabetes and might contribute to healthy longevity.

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Celastrol prevents high‐fat diet‐induced obesity by promoting white adipose tissue browning

Clinical and Translational Medicine ◽

10.1002/ctm2.641 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Bingwei Wang ◽

Xiaoning Yang ◽

Miao Zhao ◽

Zhijie Su ◽

Zhiping Hu ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity ◽

Tissue Browning

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Abstract 275: High Fat Diet-induced Decreases In Insulin Signaling In Afferent Renal Nerves Are Prevented By Intrathecal Injection Of Metformin In Rats

Hypertension ◽

10.1161/hyp.64.suppl_1.275 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Shuang-Quan Yu ◽

Donna H Wang

Keyword(s):

Insulin Receptor ◽

Insulin Signaling ◽

High Fat Diet ◽

Intrathecal Injection ◽

Renal Nerves ◽

Insulin Receptor Substrate ◽

High Fat ◽

Insulin Receptor Substrate 1 ◽

Glut 1 ◽

Trpv1 Channels

Metformin, an anti-type 2 diabetic agent that increases insulin sensitivity in target tissues, has been suggested having neuroprotective effects. Our previous data showed that metformin protects against high fat diet (HFD)-induced impairment in renal afferent nerves that express the transient receptor potential vanilloid 1 (TRPV1) channels, and prevents HFD-induced renal functional deterioration and hypertension. However, mechanisms of metformin-mediated neuroprotection are largely unknown. This study tests the hypothesis that HFD impairs insulin signaling in afferent renal nerves, which is prevented by metformin via the pathway of IRS-1-tyr, AMPK, and GLUT-1/3. Metformin (1 ng/kg, daily intrathecal injection via indwelled catheters to segments T8-L3 supplying the kidneys) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Immunohistochemical staining showed that insulin receptor substrate-1 phosphorylated with serine (p-IRS-1-ser), insulin receptor substrate-1 phosphorylated with tyrosine (p-IRS-1-tyr), phosphorylated AMP-activated protein kinase (p-AMPK), glucose transporter 1 (GLUT-1), and GLUT-3 were expressed in dorsal root ganglia (DRG). Levels of p-IRS-1-ser were increased by HFD but decreased by metformin in Con rats, and HFD-induced increases in p-IRS-1-ser were prevented by metformin. Levels of p-IRS-1-tyr, p-AMPK, and the trafficking of GLUT-1 and GLUT-3 from cytoplasma to cell membrane in DRG were decreased by HFD but increased by metformin in Con rats, and HFD-induced decreases in these parameters were prevented by metformin (p-IRS-1-tyr, Con: 0.23±0.02, Con+Met: 0.34±0.04, HFD: 0.14±0.02, HFD+Met: 0.22±0.03, p<0.05). Afferent renal nerve activity (ARNA) in response to insulin perfusion into the renal pelvis was decreased by HFD but enhanced by metformin in Con rats, and HFD-induced decreases in ARNA was prevented by metformin. Our data showed that HFD decreases insulin signaling in afferent renal nerves, which is prevented by metformin injected intrathecally to segments innervating kidneys. These data indicate that metformin may constitute neuroprotecitve effects via improving insulin signaling in afferent renal nerves via activation of the pathway of IRS-1-tyr, AMPK, and GLUT-1/3.

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Emodin Protects against High-Fat Diet-Induced Obesity via Regulation of AMP-Activated Protein Kinase Pathways in White Adipose Tissue

Planta Medica ◽

10.1055/s-0031-1298626 ◽

2012 ◽

Vol 78 (10) ◽

pp. 943-950 ◽

Cited By ~ 14

Author(s):

Thing-Fong Tzeng ◽

Hung-Jen Lu ◽

Shorong-Shii Liou ◽

Chia Chang ◽

I-Min Liu

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

White Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity ◽

Amp Activated Protein Kinase

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Galectin-3 Activates PPARγ and Supports White Adipose Tissue Formation and High-Fat Diet-Induced Obesity

Endocrinology ◽

10.1210/en.2014-1374 ◽

2015 ◽

Vol 156 (1) ◽

pp. 147-156 ◽

Cited By ~ 40

Author(s):

Jung-Hwan Baek ◽

Seok-Jun Kim ◽

Hyeok Gu Kang ◽

Hyun-Woo Lee ◽

Jung-Hoon Kim ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

Tissue Formation ◽

High Fat ◽

Diet Induced Obesity ◽

Galectin 3

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The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet

Scientific Reports ◽

10.1038/s41598-020-59284-w ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Jessica E. C. Jones ◽

Nabil Rabhi ◽

Joseph Orofino ◽

Ramya Gamini ◽

Valentina Perissi ◽

...

Keyword(s):

Adipose Tissue ◽

Transcription Factors ◽

Focal Adhesion ◽

White Adipose Tissue ◽

Transcriptome Analysis ◽

High Fat Diet ◽

High Fat ◽

Transcriptional Signature ◽

Diet Induced Obesity ◽

Enhanced Expression

AbstractVisceral white adipose tissue (vWAT) expands and undergoes extensive remodeling during diet-induced obesity. Much is known about the contribution of various stromal vascular cells to the remodeling process, but less is known of the changes that occur within the adipocyte as it becomes progressively dysfunctional. Here, we performed a transcriptome analysis of isolated vWAT adipocytes to assess global pathway changes occurring in response to a chronic high fat diet (HFD). The data demonstrate that the adipocyte responds to the HFD by adopting a fibroblast-like phenotype, characterized by enhanced expression of ECM, focal adhesion and cytoskeletal genes and suppression of many adipocyte programs most notably those associated with mitochondria. This study reveals that during obesity the adipocyte progressively becomes metabolically dysfunctional due to its acquisition of fibrogenic functions. We propose that mechano-responsive transcription factors such as MRTFA and SRF contribute to both upregulation of morphological genes as well as suppression of mitochondrial programs.

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