Secretin receptor‐knockout mice are resistant to high‐fat diet‐induced obesity and exhibit impaired intestinal lipid absorption

Abstract ATP6AP2 expression is increased in the nephron during high fat diet (HFD) and its knockout (ATP6AP2 KO) reduces body weight (WT) in mice. We evaluated the contribution of ATP6AP2 to urinary glucose (UG) and albumin (Ualb) handling during HFD. We hypothesized that nephron ATP6AP2 KO increases UG and Ualb and minimizes HFD-induced obesity. Eight-week old male C57BL/6J mice with inducible nephron specific ATP6AP2 KO and non-induced controls (C) were fed either normal diet (ND, 12% kcal fat) or HFD (45% kcal fat) for 6 months. ATP6AP2 KO mice on ND had 20% (p<0.01) lower WT compared to C. HFD fed mice had 41% (p<0.05) greater WT than ND fed C. In contrast, ATP6AP2 KO abrogated the increase in WT induced by HFD by 40% (p<0.05). Mice on HFD had less caloric intake compared to ND controls (p<0.01). There were no significant differences in metabolic rate between all groups. UG and Ualb was significantly increased in ATP6AP2 KO mice on both ND and HFD. ATP6AP2 KO showed greater levels of proximal tubule apoptosis and histologic evidence of proximal tubule injury. In conclusion, our results demonstrate that nephron specific ATP6AP2 KO is associated with glucosuria and albuminuria, most likely secondary to renal proximal tubule injury and/or dysfunction. Urinary loss of nutrients may have contributed to the reduced WT of knockout mice on ND and lack of WT gain in response to HFD. Future investigation should elucidate the mechanisms by which loss of renal ATP6AP2 causes proximal tubule injury and dysfunction.

Download Full-text

Supplementation with Sea Vegetables Palmaria mollis and Undaria pinnatifida Exerts Metabolic Benefits in Diet-Induced Obesity in Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzaa072 ◽

2020 ◽

Vol 4 (5) ◽

Cited By ~ 1

Author(s):

Rufa L Mendez ◽

Cristobal Miranda ◽

Courtney R Armour ◽

Thomas J Sharpton ◽

Jan Frederik Stevens ◽

...

Keyword(s):

Gut Microbiome ◽

High Fat Diet ◽

Undaria Pinnatifida ◽

Lipid Absorption ◽

Health Improvement ◽

High Fat ◽

Metabolic Complications ◽

Diet Induced Obesity ◽

Sea Vegetables ◽

Lipid Excretion

ABSTRACT Background Sea vegetables are rich sources of nutrients as well as bioactive components that are linked to metabolic health improvement. Algal polysaccharides improve satiety and modulate gut microbiota while proteins, peptides, and phenolic fractions exert anti-inflammatory, antioxidant, and antidiabetic effects. Objective We tested the hypothesis that dietary supplementation with either Pacific dulse (Palmaria mollis, red algae) or wakame (Undaria pinnatifida, brown algae) could remediate metabolic complications in high-fat diet-induced obesity. Methods Individually caged C57BL/6J mice (n = 8) were fed ad libitum with either a low-fat diet (LFD), 10% kcal fat; high-fat diet (HFD), 60% kcal fat; HFD + 5% (wt:wt) dulse (HFD + D); or HFD + 5% (wt:wt) wakame (HFD + W) for 8 weeks. Food intake and weight gain were monitored weekly. Glucose tolerance, hepatic lipids, fecal lipids, and plasma markers were evaluated, and the gut microbiome composition was assessed. Results Despite the tendency of higher food and caloric intake than the HFD (P = 0.04) group, the HFD + D group mice did not exhibit higher body weight, indicating lower food and caloric efficiency (P < 0.001). Sea vegetable supplementation reduced plasma monocyte chemotactic protein (MCP-1) (P < 0.001) and increased fecal lipid excretion (P < 0.001). Gut microbiome analysis showed that the HFD + D group had higher alpha-diversity than the HFD or LFD group, whereas beta-diversity analyses indicated that sea vegetable–supplemented HFD-fed mice (HFD + D and HFD + W groups) developed microbiome compositions more similar to those of the LFD-fed mice than those of the HFD-fed mice. Conclusion Sea vegetable supplementation showed protective effects against obesity-associated metabolic complications in C57BL/6J male mice by increasing lipid excretion, reducing systemic inflammatory marker, and mitigating gut microbiome alteration. While the obese phenotype development was not prevented, metabolic issues related to lipid absorption, inflammation, and gut microbial balance were improved, showing therapeutic promise and warranting eventual mechanistic elucidations.

Download Full-text

Cholecystokinin Knockout Mice Are Resistant to High-Fat Diet-Induced Obesity

Gastroenterology ◽

10.1053/j.gastro.2010.01.044 ◽

2010 ◽

Vol 138 (5) ◽

pp. 1997-2005 ◽

Cited By ~ 38

Author(s):

Chun–Min Lo ◽

Alexandra King ◽

Linda C. Samuelson ◽

Tammy Lyn Kindel ◽

Therese Rider ◽

...

Keyword(s):

Knockout Mice ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity

Download Full-text

Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption

Scientific Reports ◽

10.1038/s41598-017-05951-4 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Siva S. V. P. Sakamuri ◽

Russell Watts ◽

Abhijit Takawale ◽

Xiuhua Wang ◽

Samuel Hernandez-Anzaldo ◽

...

Keyword(s):

High Fat Diet ◽

Tissue Inhibitor Of Metalloproteinase ◽

Lipid Absorption ◽

High Fat ◽

Tissue Inhibitor ◽

Diet Induced Obesity ◽

Obesity In Mice

Download Full-text

Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and lipid absorption in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019388118 ◽

2021 ◽

Vol 118 (6) ◽

pp. e2019388118

Author(s):

Lili Ding ◽

Eryun Zhang ◽

Qiaoling Yang ◽

Lihua Jin ◽

Kyle M. Sousa ◽

...

Keyword(s):

Sleeve Gastrectomy ◽

Bile Acids ◽

Knockout Mice ◽

High Fat Diet ◽

Lipid Absorption ◽

Metabolic Effects ◽

Fat Absorption ◽

Vertical Sleeve Gastrectomy ◽

High Fat ◽

Beneficial Effects

Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (Fxr) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific Fxr knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (Bsep) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat absorption. These findings were verified in sterol 27-hydroxylase (Cyp27a1) knockout mice, which exhibited low intestinal BAs and fat absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and lipid absorption contribute to the metabolic benefits of VSG.

Download Full-text

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity

International Journal of Molecular Sciences ◽

10.3390/ijms22031139 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1139

Author(s):

Shing-Hwa Liu ◽

Rui-Yi Chen ◽

Meng-Tsan Chiang

Keyword(s):

Lipid Peroxidation ◽

High Fat Diet ◽

Control Diet ◽

Liver Lipid ◽

Lipid Absorption ◽

Chitosan Oligosaccharide ◽

Hepatic Lipogenesis ◽

High Fat ◽

Diet Induced Obesity ◽

Liver Lipid Peroxidation

Chitosan and its derivative, chitosan oligosaccharide (CO), possess hypolipidemic and anti-obesity effects. However, it is still unclear if the mechanisms are different or similar between chitosan and CO. This study was designed to investigate and compare the effects of CO and high-molecular-weight chitosan (HC) on liver lipogenesis and lipid peroxidation, adipose lipolysis, and intestinal lipid absorption in high-fat (HF) diet-fed rats for 12 weeks. Rats were divided into four groups: normal control diet (NC), HF diet, HF diet+5% HC, and HF diet+5% CO. Both HC and CO supplementation could reduce liver lipid biosynthesis, but HC had a better effect than CO on improving liver lipid accumulation in HF diet-fed rats. The increased levels of triglyceride decreased lipolysis rate, and increased lipoprotein lipase activity in the perirenal adipose tissue of HF diet-fed rats could be significantly reversed by both HC and CO supplementation. HC, but not CO, supplementation promoted liver antioxidant enzymes glutathione peroxidase and superoxide dismutase activities and reduced liver lipid peroxidation. In the intestines, CO, but not HC, supplementation reduced lipid absorption by reducing the expression of fabp2 and fatp4 mRNA. These results suggest that HC and CO have different mechanisms for improving lipid metabolism in HF diet-fed rats.

Download Full-text