Role of autophagy in a model of obesity: A long‑term high fat diet induces cardiac dysfunction

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

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Long term effects of high fat diet given early in life in prenatally stressed rats: role of the inflammatory response

10.26226/morressier.5b681761b56e9b005965c755 ◽

2018 ◽

Author(s):

Mazzelli Monica ◽

Veronica Begni ◽

Marco Andrea Riva ◽

Annamaria Cattaneo

Keyword(s):

Inflammatory Response ◽

High Fat Diet ◽

Long Term Effects ◽

High Fat ◽

Prenatally Stressed

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Abstract 41: Cardiomyocyte-specific Conditional Deletion of GSK-3β Leads to Cardiac Dysfunction in a High Fat Diet Induced Obesity Model

Circulation Research ◽

10.1161/res.121.suppl_1.41 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Manisha Gupte ◽

Samvruta Tumuluru ◽

Anand P Singh ◽

Prachi Umbarkar ◽

Qinkun Zhang ◽

...

Keyword(s):

Cardiac Function ◽

Fat Mass ◽

Cardiac Dysfunction ◽

High Fat Diet ◽

Ventricular Dysfunction ◽

Heart Weight ◽

High Fat ◽

Apoptotic Protein ◽

Gsk 3Β

Introduction: Previous studies from our group have demonstrated that cardiac myocyte glycogen synthase kinase-3’s (GSK-3) are required to maintain normal cardiac physiology. Adult mice lacking both isoforms of GSK-3 (α and β) in cardiac myocytes exhibit excessive dilatative remodeling and ventricular dysfunction ultimately leading to death. While high fat diet (HFD) induced obesity is associated with increased risk of cardiovascular disease, the specific role of cardiac GSK-3α or GSK-3β in obesity-associated cardiac dysfunction is unknown. Objective: The primary goal of the present study was to investigate the role of cardiomyocyte GSK-3β in cardiac homeostasis in HFD-induced chronic obesity model. Method: Cardiomyocyte specific-GSK-3β knock out (CM-GSK-3βKO) and wild type (WT) mice were fed either a chow (11.5% calories from fat) or high-fat (60% calories from fat) for 24 weeks. Cardiac function was accessed by non-invasive transthoracic echocardiography. Results: HFD significantly increased body weight, lean and fat mass in the WT and CM-GSK-3βKO compared to chow. However, there was no difference in body weights, lean and fat mass between the two genotypes fed either a chow or HFD. Furthermore, ventricular chamber dimensions and cardiac function were comparable between the WT and CM-GSK-3βKO mice fed a chow diet. In contrast, high fat fed CM-GSK-3βKO hearts exhibit significant cardiac hypertrophy (heart weight/tibia length ratio) and ventricular dysfunction (reduced ejection fraction (EF) and fractional shortening (FS)) compared to the WT. Interestingly cardiomyocytes from HF fed CM-GSK-3βKO exhibit structural abnormalities and increased expression of pro-apoptotic protein Bax and reduced expression of Bcl-2, an anti-apoptotic protein. Conclusion: In summary, these data suggests that cardiac GSK-3β is important in the setting of HFD-induced chronic obesity to maintain cardiac function. In the absence of GSK-3β, cardiomyocytes undergo morphometric abnormalities, excessive fat infiltration and apoptosis leading to cardiac dysfunction.

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Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity

Neuroendocrinology ◽

10.1159/000491018 ◽

2018 ◽

Vol 107 (2) ◽

pp. 147-157 ◽

Cited By ~ 3

Author(s):

Sheng-Feng Tsai ◽

Hung-Tsung Wu ◽

Pei-Chun Chen ◽

Yun-Wen Chen ◽

Megan Yu ◽

...

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Tissue Expansion ◽

Plasma Corticosterone ◽

High Fat ◽

Obesity In Mice ◽

Bilateral Lesions

Background: The notion that exposure to chronic stress predisposes individuals to developing type 2 diabetes (T2D) has gained much attention in recent decades. Long-term stress induces neuroadaptation in the amygdala and increases corticosterone levels. Corticosterone, the major stress hormone in rodents, induces insulin resistance and obesity in mice. However, little is known about whether the stress-induced amygdalar neuroadaptation could promote the risk of T2D. Methods: We used an 11-week high-fat diet (HFD) feeding paradigm to induce insulin dysfunction in mice, followed by implementation of a 10-day social defeat (SD) stress protocol. Results: Mice receiving SD at the beginning of the HFD feeding aggravated HFD-induced insulin resistance and white adipose tissue expansion. HFD mice had higher levels of plasma corticosterone, which was not affected by the SD. The SD stress upregulated the expression of TrkB and synaptotagmin-4 in the amygdala of HFD mice. Bilateral lesions of the central amygdalae before SD stress inhibited the stress-induced aggravating effect without affecting the HFD-induced elevation of plasma corticosterone. Conclusions: Stress aggravates HFD-induced insulin resistance and neuroadaptation in the amygdala. The HFD-induced insulin resistance is amygdala-dependent. Understanding the role of stress-induced amygdalar adaptation in the development of T2D could inform therapies aimed at reducing chronic stressors to decrease the risk for T2D.

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