Nawfal W. Istfan

Objective: Incretin‐based obesity therapies (IBTs), especially GLP‐1 receptor agonists (GLP‐1 RAs), effectively treat obesity and improve comorbidities. However, their impact on energy metabolism is unclear. A recent case of acute generalized muscle weakness in a patient with mitochondrial myopathy after tirzepatide exposure raises concerns about IBTs' potential to uncouple oxidative phosphorylation (OXPHOS). Given the widespread use of IBTs, this inquiry is crucial due to potential adverse effects. Methods: A narrative literature review of evidence linking incretins and IBTs to mitochondrial physiology, bioenergetics, and OXPHOS was conducted. Results: Early research on incretin physiology focused on insulin secretion in pancreatic β‐cells. However, GLP‐1 counteracts insulin signaling during excessive nutrient delivery by activating anti‐inflammatory pathways associated with fasting, suggesting it mitigates the adverse effects of overfeeding. Preclinical studies show that IBTs activate thermogenic genes and uncoupling proteins. Conclusions: We have identified indirect evidence suggesting that IBTs may induce OXPHOS uncoupling. We propose a testable hypothesis that establishes a close relationship between the distinct effects of IBTs on weight loss and their direct reduction of oxidative stress. Should this hypothesis be validated, it would enhance our comprehension of the physiology underlying IBTs and the potential adverse effects on muscle.

This article introduces the second law of thermodynamics as an integral component of the study of human energy metabolism. The concepts of efficiency and energy dissipation are unified with the current understanding of energy balance in human subjects. It is important to note that the energy utilized in biological processes constitutes only a fraction of the total energy metabolism. Measurement of this fraction relative to total energy expenditure elucidates the body’s mechanisms for adapting to fuel scarcity and abundance, as exemplified by weight gain and weight loss.

The discovery of leptin has heralded the beginning of decades of significant research contributing to our understanding of the system that governs energy homeostasis and the pathways that modulate appetite, satiety, and metabolism. The complex neuronal circuits that receive hormonal and signaling input from the gut, adipose tissue, pancreas, and other organs; and secrete neurotransmitters and peptides in order to integrate information about energy intake and expenditure with the ultimate goal of regulating body weight. Anti-obesity medications (AOMs) that are currently in use utilize these pathways to create a negative energy balance that promotes weight loss. The goal of using AOMs is to promote sustainable weight loss and thereby prevention of obesity complications. AOMs currently used in the clinical setting work via decreasing appetite and increasing satiety with a net effect of decreased food intake rather than increasing energy expenditure. The investigation and promotion of safety and tolerability of drugs which increase energy expenditure has been elusive due to the inevitable increased peripheral sympathetic tone, which generally results in intolerable side effects such as increased heart rate, blood pressure, and increased myocardial oxygen demand. Hence, this chapter will focus on the mechanisms by which current anti-obesity agents regulate energy intake.

Current principles assume that conversion of thermic energy to metabolically useful energy follows fixed rules. These principles ignore the possibility of variable proton uncoupling in mitochondria. Our study shows that the net balance of electron distribution between mitochondria and cytoplasm is influenced by insulin in a manner that reduces the need for proton leakage during overfeeding. Characterization of the effects of insulin on redox balance is important for understanding obesity and insulin resistance.

Context: Weight regain (WR) after bariatric surgery is emerging as a common clinical problem due to the increase in the number of procedures performed. Early interventions are necessary to curtail the potential recurrence of comorbid conditions. However, it is often difficult to recognize WR early enough to introduce mitigating measures because there are no current guidelines for timely diagnosis and assessment of the severity of this condition. Objective: We present a practical approach for the early recognition of WR, based on 11-year follow-up data from our multiethnic bariatric surgery patient population. Methods: We classify WR according to the rate of increase in weight relative to nadir weight, normalized per 30-day interval. We also review pertinent literature about the etiologic factors contributing to WR after bariatric surgery. Results: According to our algorithm, mild, moderate, and rapid WR are defined as weight increases of 0.2% to <0.5%, 0.5% to 1.0%, and more than 1.0% of nadir weight per 30 days, respectively. Treatment options, including dietary counseling, use of antiobesity medication, and consideration of surgical revision, are described. A case is presented to illustrate the utility of timely identification of WR and the importance of collaboration between bariatric surgeons, obesity medicine specialists, and dietitians. Conclusion: Our approach emphasizes the importance of regular long-term follow-up for all bariatric surgery patients.

Objective: Weight regain (WR) after Roux‐en‐Y gastric bypass surgery (RYGB) starts to occur 2 years after surgery, ultimately affecting at least 25% of patients. A limited number of studies have evaluated the impact of antiobesity medications (AOMs) on this phenomenon.Methods: This study reviewed the electronic medical records of 1,196 patients who underwent RYGB between 2004 and 2015. WR was evaluated by comparing each patient’s weight during subsequent postoperative office visits to nadir weight (lowest weight after RYGB, n = 760), taking into consideration the interval during which WR occurred. Patients who were prescribed AOMs and came to follow‐up visits were classified as adherent users, whereas those who missed their follow‐up visits were considered nonadherent. This study used a linear mixed model, Cox regression, and generalized equation estimator to determine the impact of AOMs on WR trajectory, hazard ratio for time to event, and odds ratio for repeated event occurrence, respectively.Results: Despite the lack of a unified protocol for using AOMs, the three statistical models converged to show that phentermine and topiramate, used individually or in combination, can significantly reduce WR after RYGB.Conclusions: Phentermine and topiramate are effective in mitigating WR after RYGB. Further studies are needed to help ascertain optimal use of AOMs after bariatric surgery.

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its metabolic consequences. The data used in this narrative review were collected through research in PubMed and reference review of relevant retrieved articles. Insulin secretion and clearance are regulated processes that influence the development and progression of hyperinsulinemia. Environmental, genetic, and dietary factors are associated with hyperinsulinemia. Certain pharmacotherapies for obesity and bariatric surgery are effective at mitigating hyperinsulinemia and are associated with improved metabolic health. Hyperinsulinemia is associated with many environmental and genetic factors that interact with a wide network of hormones. Recent studies have advanced our understanding of the factors affecting insulin secretion and clearance. Further basic and translational work on hyperinsulinemia may allow for earlier and more personalized treatments for obesity and metabolic diseases.