4261 Insulin Sensitizing Effects of Vitamin D Mediated through Reduced Adipose Tissue Inflammation and Fibrosis: Evidence from a Human Randomized Trial and Mice Studies

OBJECTIVES/GOALS: Vitamin D [25(OH)D], known to have anti-inflammatory and anti-fibrotic effects in other tissues, may also impact adipose tissue. We designed parallel studies in humans and rodents to define the effects of vitamin D on adipose tissue inflammation and fibrosis, and on systemic insulin resistance. METHODS/STUDY POPULATION: We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D at to two levels (to >30 ng/ml and to > 50 ng/ml) in 25(OH)D-deficient (<20 ng/ml), insulin resistant, overweight-to-obese humans (n = 19). A comprehensive study of whole-body insulin action was undertaken with euglycemic stepped hyperinsulinemic clamp studies, both before (1st visit) and after administration of vitamin D or placebo (2nd visit and 3rd visit). Adipose tissue fibrosis and inflammation were quantified by ‘real-time’ rt-PCR and immunofluorescence. To determine whether vitamin D’s effects are mediated through adipocytes, we performed hyperinsulinemic clamp studies and adipose tissue analysis in an adipocyte-specific vitamin D receptor knockout (VDR KO) mouse model. RESULTS/ANTICIPATED RESULTS: 25(OH)D repletion (to >30 ng/ml) was associated with reductions in adipose tissue expression of inflammatory (0.6-0.7-fold decreased expression of TNF-α, IL-6, iNOS and PAI-1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGF-β1, HiF1α, Collagen I, V, VI and MMP7) factors, decreased collagen VI immunofluorescence (p = 0.02) and improved hepatic insulin sensitivity in humans, with suppression of endogenous glucose production (EGP) (1.28 ± 0.20 vs 0.88 ± 0.18 mg/kg/min, p = 0.03). Compared to wild type (WT), VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-α, iNos, Pai-1, Mcp-1 and F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-β1, Collagen VI, and Tsp1; 2-4 fold), in concert with hepatic insulin resistance (EGP 10 ± 3 vs 3 ± 2 mg/kg/min in WT, p = 0.021). DISCUSSION/SIGNIFICANCE OF IMPACT: Collectively, these complementary human and rodent studies establish a beneficial role of vitamin D to improve hepatic insulin resistance, likely by restraining adipose tissue inflammation and fibrosis. Thus, normalizing 25(OH)D levels could have metabolic benefits in targeted individuals. CONFLICT OF INTEREST DESCRIPTION: N/A

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Interleukin-1β May Mediate Insulin Resistance in Liver-Derived Cells in Response to Adipocyte Inflammation

Endocrinology ◽

10.1210/en.2010-0340 ◽

2010 ◽

Vol 151 (9) ◽

pp. 4247-4256 ◽

Cited By ~ 69

Author(s):

Ori Nov ◽

Ayelet Kohl ◽

Eli C. Lewis ◽

Nava Bashan ◽

Irit Dvir ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Receptor ◽

Receptor Antagonist ◽

Glycogen Synthase ◽

Liver Cells ◽

Hepatic Insulin Resistance ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation

Central obesity is frequently associated with adipose tissue inflammation and hepatic insulin resistance. To identify potential individual mediators in this process, we used in vitro systems and assessed if insulin resistance in liver cells could be induced by secreted products from adipocytes preexposed to an inflammatory stimulus. Conditioned medium from 3T3-L1 adipocytes pretreated without (CM) or with TNFα (CM-TNFα) was used to treat Fao hepatoma cells. ELISAs were used to assess the concentration of several inflammatory mediators in CM-TNFα. CM-TNFα-treated Fao cells exhibited about 45% diminution in insulin-stimulated phosphorylation of insulin receptor, insulin receptor substrate proteins, protein kinase B, and glycogen synthase kinase-3 as compared with CM-treated cells, without changes in the total abundance of these protein. Insulin increased glycogenesis by 2-fold in CM-treated Fao cells but not in cells exposed to CM-TNFα. Expression of IL-1β mRNA was elevated 3-fold in TNFα-treated adipocytes, and CM-TNFα had 10-fold higher concentrations of IL-1β but not TNFα or IL-1α. IL-1β directly induced insulin resistance in Fao, HepG2, and in primary rat hepatocytes. Moreover, when TNFα-induced secretion/production of IL-1β from adipocytes was inhibited by the IL-1 converting enzyme (ICE-1) inhibitor II (Ac-YVAD-CMK), insulin resistance was prevented. Furthermore, liver-derived cells treated with IL-1 receptor antagonist were protected against insulin resistance induced by CM-TNFα. Finally, IL-1β secretion from human omental fat explants correlated with body mass index (R2 = 0.639, P < 0.01), and the resulting CM induced insulin resistance in HepG2 cells, inhibitable by IL-1 receptor antagonist. Our results suggest that adipocyte-derived IL-1β may constitute a mediator in the perturbed cross talk between adipocytes and liver cells in response to adipose tissue inflammation.

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Effects of exercise and low-fat diet on adipose tissue inflammation and metabolic complications in obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00054.2009 ◽

2009 ◽

Vol 296 (5) ◽

pp. E1164-E1171 ◽

Cited By ~ 121

Author(s):

Victoria J. Vieira ◽

Rudy J. Valentine ◽

Kenneth R. Wilund ◽

Nirav Antao ◽

Tracy Baynard ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Adipose Tissue Inflammation ◽

Obese Mice ◽

Metabolic Disturbances ◽

Low Fat ◽

Tissue Inflammation ◽

Low Fat Diet ◽

Tnf Α

Adipose tissue inflammation causes metabolic disturbances, including insulin resistance and hepatic steatosis. Exercise training (EX) may decrease adipose tissue inflammation, thereby ameliorating such disturbances, even in the absence of fat loss. The purpose of this study was to 1) compare the effects of low-fat diet (LFD), EX, and their combination on inflammation, insulin resistance, and hepatic steatosis in high-fat diet-induced obese mice and 2) determine the effect of intervention duration (i.e., 6 vs. 12 wk). C57BL/6 mice ( n = 109) fed a 45% fat diet (HFD) for 6 wk were randomly assigned to an EX (treadmill: 5 days/wk, 6 or 12 wk, 40 min/day, 65–70% V̇o2max) or sedentary (SED) group. Mice remained on HFD or were placed on a 10% fat diet (LFD) for 6 or 12 wk. Following interventions, fat pads were weighed and expressed relative to body weight; hepatic steatosis was assessed by total liver triglyceride and insulin resistance by HOMA-IR and glucose AUC. RT-PCR was used to determine adipose gene expression of MCP-1, F4/80, TNF-α, and leptin. By 12 wk, MCP-1, F4/80, and TNF-α mRNA were reduced by EX and LFD. Exercise ( P = 0.02), adiposity ( P = 0.03), and adipose F4/80 ( P = 0.02) predicted reductions in HOMA-IR ( r2 = 0.75, P < 0.001); only adiposity ( P = 0.04) predicted improvements in hepatic steatosis ( r2 = 0.51, P < 0.001). Compared with LFD, EX attenuated increases in adiposity, hepatic steatosis, and adipose MCP-1 expression from 6 to 12 wk. There are unique metabolic consequences of a sedentary lifestyle and HFD that are most evident long term, highlighting the importance of both EX and LFD in preventing obesity-related metabolic disturbances.

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Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

10.2337/figshare.12582794 ◽

2020 ◽

Author(s):

Ada Admin ◽

Mara A. Dedual ◽

Stephan Wueest ◽

Tenagne D. Challa ◽

Fabrizio C. Lucchini ◽

...

Keyword(s):

Adipose Tissue ◽

Mrna Expression ◽

Cystatin C ◽

Tissue Expression ◽

Hepatic Insulin Resistance ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Relationship Of ◽

Inflammatory Macrophage ◽

Macrophage Accumulation

We recently demonstrated that removal of one kidney (uninephrectomy; UniNx) in mice reduced high fat-diet (HFD)-induced adipose tissue inflammation thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared to sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown herein in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC KO) mice deteriorated obesity-associated adipose tissue inflammation and dysfunction, as assessed by pro-inflammatory macrophage accumulation. In addition, mRNA expression of pro-inflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similarly to findings in adipose tissue, expression of pro-inflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in knockout mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide (LPS)-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL-6 mRNA expression. Moreover, healthy (i.e. insulin-sensitive) subjects with obesity depicted significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism.

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Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00179.2013 ◽

2013 ◽

Vol 305 (3) ◽

pp. E388-E395 ◽

Cited By ~ 41

Author(s):

Michael S. F. Wiedemann ◽

Stephan Wueest ◽

Flurin Item ◽

Eugen J. Schoenle ◽

Daniel Konrad

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

High Fat Diet ◽

Hepatic Insulin Resistance ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Hepatic Insulin Sensitivity ◽

Tissue Inflammation

High-fat feeding for 3–4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

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