The results presented in this investigation offer a comprehensive insight into the role of Sesn2 KO in aggravating the adverse impacts of HFD on various physiological aspects in female mice. These findings highlight the importance of Sestrin2 in maintaining metabolic homeostasis and protecting against the detrimental effects of HFD-induced obesity and its associated complications.
Obesity presents a growing global health concern, imposing a significant burden on public health. Notably, metabolic responses exhibit sex-specific differences, suggesting potential greater resilience in females. In this study, we delve into this phenomenon, uncovering intriguing insights. Specifically, a 12-week HFD yielded only a modest increase in body weight in female mice. Strikingly, this HFD had minimal impact on circulating triglyceride and FFA levels, as well as glucose regulation, implying a degree of resistance to HFD-induced metabolic alterations in female mice.
Sestrin2, a stress-responsive protein, intricately links with metabolic pathways, regulating energy balance and cellular stress responses. Its central role designates Sesn2 as a potential key in addressing obesity, insulin resistance, and related complications. Its impact on pathways like AMPK-mTOR underscores its significance in coordinating cellular metabolism, holding promise for metabolic disorder treatments [19]. To elucidate Sestrin2’s contribution to the resistance of female mice against an HFD, we established obesity models in both WT and Sesn2 KO female mice using a 12-week HFD regimen. Remarkably, KO-HFD mice displayed the most pronounced increases in body weight, body fat, and fat percentage. Furthermore, elevated circulating triglycerides and FFA were evident in the KO-HFD groups. While fasting glucose levels remained comparable between WT-NC and WT-HFD groups, KO-HFD mice exhibited the highest glucose levels. Impairments in glucose homeostasis were conspicuous among the KO-HFD mice. These results emphasize Sestrin2’s crucial role in HFD-induced metabolic abnormalities in female mice.
The escalating global obesity crisis leads to excessive adipose tissue, contributing to metabolic complications like injuries for liver, heart and kidney. Intriguingly, emerging research suggests females might display heightened resilience to metabolic consequences linked with obesity. Our study aims to clarify Sestrin2’s role by probing its impact on HFD-triggered metabolic disruptions. Specifically, we assessed Sesn2 KO effects on HFD-induced hepatic injury. The absence of Sesn2 accentuated hepatic injury, evident through impaired liver function, heightened expression of inflammatory markers Ccl2 and Il6. Sestrin2 activates AMPK, leading to mTOR inhibition, effectively addressing metabolic disorders, such as insulin resistance and mitochondrial dysfunction [11, 20, 21]. Notably, Sesn2 KO hindered AMPK activation, reducing mTOR inhibition, accentuating lipid accumulation. This effect was amplified in KO-HFD mice, aligning with disrupted liver structure and inflammation, particularly in KO-HFD. These findings align with prior research indicating activating Sestrin2 mitigates obesity-related hepatic injury [17, 22].
Shifting focus to cardiac function, although HFD alone minimally affected cardiac function in female mice, Sesn2 KO coupled with an HFD regimen resulted in compromised cardiac function. This was evident from alterations in E/F and E/A ratios. Histological examination unveiled myocardial hypertrophy and significant cardiac fibrosis within the KO-HFD group. Our prior investigation highlighted Sestrin2’s significance in the cardiovascular safeguarding conferred by SGLT2 inhibitors in cases of obesity-related cardiac dysfunction [11]. These observations underscore the notion that Sesn2 deficiency exacerbates the cardiac consequences of an HFD in mice. Similarly, the impact of Sesn2 KO extended to kidney function. Within the context of HFD, Sesn2 deficiency amplified kidney dysfunction, as indicated by elevated 24-hour UAE and glomerular hypertrophy within the KO-HFD group. These outcomes strongly imply a protective role of Sestrin2 in maintaining renal health and mitigating HFD-induced kidney impairment.
Our study underscores Sestrin2’s pivotal role in regulating multi-organ responses to an HFD in female mice. Adipose tissue, traditionally deemed an energy reservoir, is now acknowledged as a dynamic endocrine organ crucial for metabolic equilibrium. However, dysfunction in adipose tissue leads to ectopic lipid accumulation in vital organs, fostering organ-specific pathologies. Central to lipid metabolism are the key enzymes LPL and ATGL, which govern triglyceride hydrolysis. While ATGL and LPL are essential for mobilizing fatty acids for energy production, increased activity of these enzymes can lead to elevated levels of FFA, which may overwhelm the capacity for beta-oxidation and contribute to insulin resistance. In obesity, elevated levels of lpl and Atgl contribute to ectopic lipid deposition [23]. Our research unveils elevated levels of these enzymes in HFD-fed mice, particularly in Sesn2 KO mice, reflecting increased lipolysis and reduced beta-oxidation, exacerbating lipotoxicity and insulin resistance. This is corroborated by elevated circulating FFA, impaired insulin sensitivity, and lower Pgc1α levels in the KO-HFD groups.
Adipose tissue, however, serves a dual purpose beyond energy storage, as it secretes adipokines [24]. A notable player among these is adiponectin, which offers protection against lipotoxicity and metabolic inflexibility [25]. Its reduction under HFD conditions, exacerbated by Sesn2 KO, aligns with aggravated inflammation. Our results indicate elevated levels of Il6 and Tnf, reflecting aggravated inflammation and weakened anti-inflammatory effects, corroborating lipid deposition and enhanced lipotoxicity in KO-HFD mice. Sestrin2 deficiency on an HFD triggers intricate shifts in energy metabolism within BAT and WAT. Notably, altered mitochondrial gene expression in BAT suggests enhanced thermogenic activity potential. In contrast, WAT displays compromised mitochondrial biogenesis, heightened inflammatory marker expression, and increased triglyceride synthesis. These collectively contribute to adipose tissue dysfunction and systemic metabolic perturbations.
UCP-1 is a pivotal protein involved in thermogenesis, particularly in BAT [26]. Lower levels of UCP-1 imply reduced thermogenesis, while higher levels of UCP-1 correlate with increased thermogenic capacity and energy expenditure. Conversely, Cidea, also primarily expressed in BAT, is associated with enhanced thermogenesis and energy expenditure [27]. Mice deficient in Cidea display heightened metabolism and elevated lipolysis, indicating an enhanced thermogenic potential [28]. Higher levels of Cidea could suggest an increased capacity for lipid storage within adipocytes. Notably, Cidea can negatively regulate UCP-1 activity [28]. Interestingly, KO-HFD mice exhibit reduced Cidea expression and increased Ucp1 levels, suggesting that the loss of UCP-1 inhibition by Cidea enhances thermogenesis and counters excessive energy accumulation. ADRB3, prevalent in adipose tissue, is implicated in energy regulation [29]. ADRB3 shields adipocytes from excessive fatty acid exposure and consequent triglyceride buildup [30]. Reduced Adrb3 and Ucp1 levels in WAT impede the transition from white to brown fat, fostering obesity. Our study shows diminished Adrb3 and Ucp1 expression in WAT in the KO-HFD group, hindering the browning process and contributing to obesity development.
PGC1α, a transcriptional coactivator, is vital for adaptive thermogenesis and energy metabolism. It promotes the expression of thermogenic genes like Ucp1 in brown adipose tissue, enhancing energy expenditure and countering obesity [31]. Additionally, PGC1α interacts with various transcription factors to regulate genes involved in energy metabolism and fatty acid oxidation, contributing to metabolic homeostasis by utilizing stored energy sources [32]. SIRT1, a deacetylase, regulates PGC1α posttranslationally. Together, they form a vital regulatory pathway influencing cellular metabolism and mitochondrial biogenesis [33]. Dysregulation of this pathway is linked to insulin resistance, abnormal lipid profiles, and various pathological conditions. In HFD-fed mice, our findings demonstrate reduced expression of Sirt1 and Pgc1α, reaching their lowest levels in KO-HFD mice. This highlights the severity of glucose and lipid metabolism dysfunction following Sesn2 KO.
Our findings highlight the intricate consequences of HFD-induced dysfunction across multiple organs, further aggravated by Sesn2 deficiency (Fig. 6). This study supports targeting Sestrin2 to mitigate obesity-related metabolic disruptions. Moreover, it unravels the complex interplay among adipose tissue, inflammation, and lipid metabolism. The observed inflammation, elevated lipid synthesis, and reduced WAT browning in HFD-fed KO mice shed light on altered adipose tissue function, impacting metabolic outcomes. While our study provides valuable insights, it has limitations. Exclusive use of female mice restricts direct generalization, urging gender-diverse investigations. While our study did not directly compare male and female KO mice, both showed susceptibility to HFD and metabolic disorders. In males, HFD exacerbated body fat percentage but not body weight compared to wild-type mice, while in females, both increased [11]. Variations in phenotype between male and female Sesn2 KO mice underscore sex-specific responses, warranting further exploration of underlying mechanisms. Additionally, despite extensive molecular exploration, deeper mechanistic insights require future research. The study’s 12-week duration may not capture long-term effects, prompting consideration for extended studies. In summary, our study highlights Sestrin2’s role, but its limitations stress the need for comprehensive, diverse, and clinically relevant investigations to validate and expand upon our findings.
Sesn2 knockout exacerbates high-fat diet induced metabolic disorders and complications in female mice
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