Date of Award

2019

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Jiang Liu, Committee Chairperson

Second Advisor

Dr. Komal Sodhi

Third Advisor

Dr. Joseph Shapiro

Fourth Advisor

Dr. Nader Abraham

Fifth Advisor

Dr. Zijian Xie

Abstract

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. It is believed that cellular oxidant stress plays a key role in both the development and maintenance of obesity as well as its associated comorbidities such as diabetes, cardiovascular disease, and nonalcoholic steatohepatitis (NASH). We have previously reported that systemic administration of pNaKtide, which targets the Na/K-ATPase oxidant amplification loop was able to decrease oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play an active role in the development of obesity and its related comorbidities, we examined whether lentiviral-mediated adipocyte-specific expression of NaKtide, the portion of pNaKtide derived from the α1 Na/K-ATPase N domain without the TAT leaders sequence used to make pNaKtide cell permeant, could have a similar ameliorative effect. To test this hypothesis, studies were first performed in isolated murine preadipocytes, 3T3-L1 cells; it was found that specific activation of Na/K-ATPase signaling (with the cardiotonic steroid ouabain which is specific to the Na/K-ATPase) significantly increased adipogenesis in 3T3-L1 cells in the presence of adipogenic medium, and pNaKtide administration attenuated oxidative stress and lipid accumulation. When administered through a lentiviral construct, NaKtide showed a similar decrease in oxidative stress. Complementary in vivo studies were performed as well. C57BL6 mice fed a WD activated adipocyte Na/K-ATPase signaling and increased adiposity, systemic oxidative stress and insulin resistance as well as induced development of NASH. Also of note, WD increased the plasma levels of leptin, IL-6 and TNFα along with decreased locomotor activity, expression of the D2 receptor and tyrosine hydroxylase in defined brain regions as well as markers of neurodegeneration including neuronal apoptosis. Selective adipocyte expression of NaKtide in these mice fed a WD attenuated all of these changes including the brain biochemical alterations and behavioral adaptations. These data suggest that adipocyte derived cytokines play an essential role in the development of obesity induced by a WD and that targeting the adipocyte Na/K-ATPase oxidant amplification loop (NKAL) may serve as an effective therapeutic strategy.

Subject(s)

Aluminum -- Physiological effect.

Obesity.

Metabolic syndrome.

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