Obesity is a significant comorbidity in many common diseases, including heart disease, diabetes, cancer, and metabolic syndrome. Usually, obesity develops when calorie intake exceeds expenditure, resulting in the excessive accumulation of body fat. The main consequence is the development of insulin resistance and lipid accumulation in the liver beyond the shift in metabolism. The liver plays a central role in energy metabolism, and impaired responses to insulin, associated with lipid deposition, contribute to steatosis and worsening insulin resistance, becoming a vicious cycle. Liver function is governed by tightly regulated and complex feedback mechanisms, including key regulators such as insulin, glucagon, and neural signals from the central nervous system. These regulatory signals help balance energy intake, storage, and expenditure, ensuring the body has an adequate energy supply to drive its demands. When that machinery is not working optimally, it creates difficulties for the body, especially when resources are limited.

Mitochondria are complex organelles that act as a hub for biosynthetic processes and have a key role in maintaining energy metabolism, particularly when associated with stress responses. Beyond its well-established role in cellular energetics, mitochondria are critical mediators of signals to propagate various cellular outcomes, such as immune responses. Mitochondria supply most of the energy for cells through adenosine triphosphate (ATP) based on dynamic nutrient metabolism. This occurs when glucose and fatty acids derived from food are oxidized via the TCA cycle. In this process, energy is conserved in chemical bonds and finally released as ATP with a reduction of nicotinamide adenine dinucleotide (NADH) and Flavin adenine dinucleotide (FADH2). The physiological importance of mitochondria is evident, as disorders of the mitochondrial respiratory chain are associated with several major diseases, and dysfunctional mitochondria have been linked to obesity, insulin resistance, and liver disease.

Recent studies have linked branched-chain amino acid (BCAA) metabolism to glucose homeostasis. Circulating levels of BCAAs and related metabolites are positively correlated with obesity and glucose intolerance, and they predict the risk of future type 2 diabetes. This research has yielded new insights that help us understand mitochondrial function in metabolism and metabolic diseases. From this, new ideas have emerged for strategies to develop therapeutic approaches. Therefore, understanding the molecular mechanisms underlying energy metabolism will facilitate new mitochondrial-targeted therapies to combat noncommunicable chronic diseases. At present, the role of mitochondria in the pathogenesis of metabolic disorders is incompletely understood.

This Research Topic aims to shed light on how the disturbance in mitochondrial function can reveal insights into the development, progression, and consequences of obesity, insulin resistance, and dysregulated energy metabolism.

For this Research Topic, the Editors welcome contributions with relevant findings in original research, reviews, short communications, case reports, clinical trials, and commentaries that cover, but are not limited to, the following themes:

1. The effects of switches in metabolism under stress conditions, such as calorie restriction, overnutrition, therapeutic strategies, physical activity.
2. Mechanisms that activate a metabolic switch and the impact on body weight control.
3. Alterations in energy metabolism in the progression of fatty liver disease.
4. The use of glucagon analogs to therapeutically regulate energy homeostasis.
5. Mitochondrial dysfunction in the progression of steatohepatitis.
6. Mitochondrial activity in the modulation of liver zonation.

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