Opposing Effects of Reduced Kidney Mass on Liver and Skeletal Muscle Insulin Sensitivity in Obese Mice

Chin, Siew Hung; Item, Flurin; Wueest, Stephan; Zhou, Zhou; Wiedemann, Michael; Gai, Zhibo; Schoenle, Eugen J.; Kullak‐Ublick, Gerd A.; Al-Hasani, Hadi; Konrad, Daniel

doi:10.2337/db14-0779

Cited by 11 publications

(9 citation statements)

References 47 publications

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“…Interestingly we showed that UniNX resulted in anti-inflammatory state in most tissues and this was associated with reduced cytokines in tissues such as liver, kidney and fat pads. Recently, it has been shown that in mouse UniNX models, tissues including fat pads showed a reduced inflammatory state (Sui et al, 2010 ; Chin et al, 2015 ). In our study in contrast, IFNγ and GM-CSF protein levels were increased in the UniNX spleen, suggesting that the increased circulating levels of these cytokines may arise from the spleen.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of SIRT1 and FXR can counter the metabolic syndrome by acting on lipid and glucose metabolism. We and others have recently shown that bile salts and their receptor FXR are modified by UniNX (Penno et al, 2013 ; Gai et al, 2014a , b ; Chin et al, 2015 ). It has also been reported that SIRT1 may regulate FXR activity (Liu et al, 2014 ).…”

Section: Introductionmentioning

confidence: 97%

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Uninephrectomy in rats on a fixed food intake results in adipose tissue lipolysis implicating spleen cytokines

et al. 2015

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The role of mild kidney dysfunction in altering lipid metabolism and promoting inflammation was investigated in uninephrectomized rats (UniNX) compared to Sham-operated controls rats. The impact of UniNX was studied 1, 2, and 4 weeks after UniNX under mild food restriction at 90% of ad libitum intake to ensure the same caloric intake in both groups. UniNX resulted in the reduction of fat pad weight. UniNX was associated with increased circulating levels of beta-hydroxybutyrate and glycerol, as well as increased fat pad mRNA of hormone sensitive lipase and adipose triglyceride lipase, suggesting enhanced lipolysis. No decrease in fat pad lipogenesis as assessed by fatty acid synthase activity was observed. Circulating hormones known to regulate lipolysis such as leptin, T3, ghrelin, insulin, corticosterone, angiotensin 1, and angiotensin 2 were not different between the two groups. In contrast, a select group of circulating lipolytic cytokines, including interferon-gamma and granulocyte macrophage–colony stimulating factor, were increased after UniNX. These cytokine levels were elevated in the spleen, but decreased in the kidney, liver, and fat pads. This could be explained by anti-inflammatory factors SIRT1, a member of the sirtuins, and the farnesoid x receptor (FXR), which were decreased in the spleen but elevated in the kidney, liver, and fat pads (inguinal and epididymal). Our study suggests that UniNX induces adipose tissue lipolysis in response to increased levels of a subset of lipolytic cytokines of splenic origin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Uninephrectomy in rats on a fixed food intake results in adipose tissue lipolysis implicating spleen cytokines

et al. 2015

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“…The area under the curve of disappearing plasma 2‐[1‐ 14 C] deoxyglucose was used together with tissue concentration of phosphorylated 2‐[1‐ 14 C] deoxyglucose to calculate glucose uptake as described previously (Chin et al . ).…”

Section: Methodsmentioning

confidence: 97%

Short‐term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high‐fat diet

Grandl

Straub

Rudigier

et al. 2018

The Journal of Physiology

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Key points A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity.KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high‐fat diet (HFD) fed animals show elevated insulin levels.A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant.Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER.Hyperinsulinaemic–euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues. AbstractDespite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a progressive increase in glucose levels, causing insulin resistance and eventual loss of glucose homeostasis. The consumption of high carbohydrate, high‐fat, western style diet (HFD) is linked to the development of T2D and obesity, whereas the consumption of a low carbohydrate, high‐fat, ketogenic diet (KD) is considered healthy. However, several days of carbohydrate restriction are known to cause selective hepatic insulin resistance. In the present study, we compare the effects of short‐term HFD and KD feeding on glucose homeostasis in mice. We show that, even though KD fed animals appear to be healthy in the fasted state, they exhibit decreased glucose tolerance to a greater extent than HFD fed animals. Furthermore, we show that this effect originates from blunted suppression of hepatic glucose production by insulin, rather than impaired glucose clearance and tissue glucose uptake. These data suggest that the early effects of HFD consumption on EGP may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP‐derived glucose.

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“…Glucose clamp studies were performed as previously described (23). Clamps were performed in freely moving mice.…”

Section: Glucose Clamp Studiesmentioning

confidence: 99%

Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

et al. 2015

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Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = 20.28, P < 0.05). The results show that IL-6 cytokineinduced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.

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Opposing Effects of Reduced Kidney Mass on Liver and Skeletal Muscle Insulin Sensitivity in Obese Mice

Cited by 11 publications

References 47 publications

Uninephrectomy in rats on a fixed food intake results in adipose tissue lipolysis implicating spleen cytokines

Uninephrectomy in rats on a fixed food intake results in adipose tissue lipolysis implicating spleen cytokines

Short‐term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high‐fat diet

Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

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