Temperature as a Control of Obesity: Can We Target Thermogenesis?

Obesity and its associated metabolic disorders have become one of the greatest health and economic problems of developed countries, and their prevalence is increasing not only in adults but also in children and adolescents (1). The past two decades have witnessed exponential growth in research dedicated to understanding metabolism and appetite control with the ultimate goal of procuring effective antiobesity drugs. It is now clear that genetic, physiological, developmental, environmental, and social causes are all intricately involved in the onset and perpetuation of the current obesity epidemic. Thus, as numerous processes and signaling mechanisms are implicated in the development and evolution of this complex disorder, it follows that the possible therapeutic targets are also numerous. Behavioral guidelines related to nutrition and physical exercise have been emphasized and implemented to an extent, and pharmacological advances have been made; however, to date these advances and interventions have not been successful in curtailing the obesity epidemic.

The pursuit of pharmaceuticals that reduce appetite, and thus energy intake and subsequently fat mass, has been the focus of a large portion of investigation and drug discovery in the field of obesity and metabolic disorders. In contrast, less has been reported regarding pharmacological modulation of the opposite side of the energy balance equation: energy expenditure. In a recent issue of Endocrinology, Lynes et al. (2) approach this subject in a timely review of lipokine activation of an important mechanism of energy expenditure: thermogenesis.

Thermogenesis is a homeostatic mechanism for the maintenance of body temperature in mammals whereby the energy stored in food is used to produce heat. This process occurs primarily in brown adipose tissue (BAT) and beige adipocytes, a more recently described cell type that develops when adipocytes in white adipose tissue acquire characteristics of brown adipocytes via a process known as browning. The previous dogma that adult humans have very little or no thermogenic adipose tissue has been dispelled in recent years, and rapid advances have been made in understanding the physiology of BAT and its implications in pathology (3).

Many genes and pathways regulate brown and beige adipocyte activity, with the hypothalamus being the main central integrator of metabolic signals and controlling the sympathetic inputs to BAT and white adipose tissue. The sympathetic nervous system is important in the control of thermogenesis; for example, increased sympathetic tone on BAT augments levels of cytosolic free fatty acids which are then imported into the mitochondria where they are used as fuel to generate heat (4). Activation of brown or beige adipose tissue has been associated with marked improvement in metabolic parameters such as levels of free fatty acids and insulin sensitivity in humans (5–7). Thus, thermogenesis is emerging as an interesting and promising target for therapeutic intervention in obesity and metabolic disease, with one aim being the discovery of mechanisms for augmenting thermogenic adipose.

A variety of signals involved in energy homeostasis can act through the sympathetic nervous system or directly on thermogenic adipose tissue to modulate its function. Here, Lynes et al. (2) discuss how lipokines, fatty acids released from adipose tissue and with metabolic effects on distant organs, may be involved in controlling thermogenesis. They present convincing arguments for various lipokines, including oleoylethanolamine (OEA), endocannabinoids, prostaglandin E2, and 12,13-diHOME as promising targets to combat metabolic disorders and improve systemic metabolism through activation of energy expenditure.

The aforementioned lipokines have been previously shown to regulate thermogenesis. The enzymes and intermediates involved in the synthesis and degradation of this selected subset of lipokines are briefly reviewed. Regulation of some of these processes by food intake, specific foods or nutrients, exercise, and cold exposure is mentioned. Furthermore, tissue-specific effects of some lipokines are discussed, but how this specificity might affect targeting of these substances for drug development is not discussed.

Interestingly, the authors highlight the rapid pharmacokinetics of these lipidic substances as an important aspect to consider in the development of drugs targeting lipokines and suggest that the focus should be placed on the synthesis and degradation machinery, or directly on the receptors, with the goal of identifying optimized pharmacokinetic ligands. However, this review does not contemplate the relationship between different lipokines, which can share part of their synthesis and/or degradation machinery. Thus, synergistic effects of these lipokines on thermoregulation could be an important aspect in their exploitation for treatment of metabolic disorders, similar to that demonstrated in the synergy of OEA with the β-adrenergic agonist CL-316,243 to activate beige adipogenesis and cause weight loss in mice (8). OEA is an endocannabinoid-like compound that, although not able to bind to cannabinoid receptors, is synthesized and degraded by the same enzymes (N-acyl phosphatidylethanolamine phospholipase D and fatty acid amide hydrolase) as are the rest of ethanolamides, such as anandamide. MGL is an enzyme involved in the production of various lipokines, including endocannabinoid 2-AG and 12,13-diHOME. Thus, targeting these enzymes, and in turn more than one pathway, could be promising for the treatment of obesity through lipokine-induced thermoregulation.

Here, Lynes et al. (2) emphasize the possible role of lipokines as a functional link between thermoregulation and metabolic disorders, adding a level of complexity to obesity and its potential treatments. This article is well written and interesting, but more than just reviewing a specific topic, it will stimulate many questions and new ideas in those interested in metabolic control and obesity treatment.

Acknowledgments

Financial Support: The authors are supported by grants from the Spanish Ministry of Science and Innovation (BFU2017-82565-C21-R2 to J.A.C.), Fondo de Investigación Sanitaria (CIBEROBN), and Fondos FEDER. P.R. holds a “Sara Borrell” research contract from the National System of Health, ISCIII, ERDF-EU (CD16/00067).

Additional Information

Disclosure Summary: The authors have nothing to disclose.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations:

Abbreviations:
 
• BAT

  brown adipose tissue

 
• OEA

  oleoylethanolamine

References and Notes