New appetite‐regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight‐loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight‐loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long‐lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

Heart rate variability (HRV) is a non-invasive indicator of autonomic nervous system function. HRV recordings show artefacts due to technical and/or biological issues. The Kubios software is one of the most used software to process HRV recordings, offering different levels of threshold-based artefact correction (i.e., Kubios filters). The aim of the study was to analyze the impact of different Kubios filters on the quantification of HRV derived parameters from short-term recordings in three independent human cohorts. A total of 312 participants were included: 107 children with overweight/obesity (10.0 ± 1.1 years, 58% men), 132 young adults (22.2 ± 2.2 years, 33% men) and 73 middle-aged adults (53.6 ± 5.2 years, 48% men). HRV was assessed using a heart rate monitor during 10–15 min, and the Kubios software was used for HRV data processing using all the Kubios filters available (i.e., 6). Repeated-measures analysis of variance indicated significant differences in HRV derived parameters in the time-domain (all p < 0.001) across the Kubios filters in all cohorts, moreover similar results were observed in the frequency-domain. When comparing two extreme Kubios filters, these statistical differences could be clinically relevant, e.g. more than 10 ms in the standard deviation of all normal R-R intervals (SDNN). In conclusion, the results of the present study suggest that the application of different Kubios filters had a significant impact on HRV derived parameters obtained from short-term recordings in both time and frequency-domains.

Background: The energy-burning capacity of brown adipose tissue (BAT) makes it an attractive target for use in anti-obesity therapies. Moreover, due to its ability to oxidize glucose and lipids, BAT activation has been considered a potential therapy to combat type 2 diabetes and atherogenesis. Summary: BAT is mainly regulated by the sympathetic nervous system (SNS); yet, recent findings have shown a group of novel activators that act independently of the stimulation of the SNS such as cardiac natriuretic peptides, irisin, interleukin-6, β-aminoisobutyric acid and fibroblast growth factor 21 that could influence BAT metabolism. Several strategies are being examined to activate and recruit BAT with no side effects. In this review, we postulate that exercise might activate and recruit human BAT through the activation of SNS, heart and skeletal muscle. Key Messages: Epidemiological and well-designed exercise-based randomized controlled studies are needed to clarify if exercise is able to activate BAT in humans.