Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

Abstract

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

Keywords: adipocyte; adrenergic receptor; energy expenditure; energy metabolism; imaging; metabolic disorder; obesity; pharmacology; sympathomimetic; thermogenesis.

Figure 1.

Sources of human thermogenesis and pharmacological approaches to increase it. There are three principal sources of thermogenesis in adult humans. Most derive from the BMR, which is the minimum energy required to perform all the basic chemical reactions of the body and is the primary contributor (60–75%) to total energy expenditure in an adult human. Movement-related thermogenesis includes exercise and nonexercise activity thermogenesis (10–30%). Adaptive thermogenesis is a physiological feedback system in which energy demands are assessed over a longer period of time, and the body responds by increasing energy expenditure. A related but different process is facultative thermogenesis, which is a temporary increase in energy expenditure only when extra heat is required acutely, such as for defending body temperature. There are three principal pharmacological approaches to stimulating human thermogenesis that use some combination of appetite suppression, impaired absorption of ingested food, and increased energy expenditure. Adapted from Ref. .

Figure 2.

Summary of brown adipose tissue, white adipose tissue, and skeletal muscle characteristics and mechanisms related to thermogenesis. Molecular, cellular, and physiological characteristics are shown in lightface text, and the molecular mechanisms are shown in bold text. Brown adipose tissue, white adipose tissue, and skeletal muscle are represented by brown, yellow, and red circles, respectively. Characteristics and mechanisms relevant to two or three tissues are shown in regions where the circles overlap.

Figure 3.

Molecular mechanisms underlying adaptive cellular thermogenesis. Mechanisms relevant to coupled respiration, which occurs in most tissues, are illustrated within the box. In the mitochondrial inner membrane, succinate dehydrogenase (SDH) forms complex II of the ETC and is one of the enzymes of the TCA cycle. Brown adipocytes expressing uncoupling protein 1 (UCP1) in response to β-adrenergic signaling can uncouple the tricarboxylic acid cycle (TCA) and oxidative phosphorylation by the electron transport chain, composed of coenzyme Q (CoQ), cytochrome c (Cyt C), and complexes I–IV, increasing the rates of the associated exergonic reactions and generating heat instead of harnessing it to make ATP. In beige/brite fat, thermogenic hydrolysis of ETC-generated ATP occurs when the mitochondrial ADP/ATP carrier transports ATP from the mitochondrial matrix into the intermembrane space where mitochondrial CK (Mi-CK) catalyzes the conversion of creatine to phosphocreatine, which is then hydrolyzed by enzymes to generate heat.

Figure 4.

Muscle-specific mechanisms of thermogenesis and therapies that can increase thermogenesis. Repeated excitation–contraction cycling with actin and myosin is stimulated by the release of sarcoplasmic calcium through the ryanodine receptor and is used by skeletal muscle for shivering thermogenesis. Muscular nonshivering thermogenesis is mediated by sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and sarcolipin. Triglyceride/fatty acid synthesis and lipolysis, which occur in skeletal muscle and other tissues, are parts of a thermogenic futile cycle. Certain therapies, such as β3-adrenergic receptor agonists, up-regulate cellular signaling pathways that lead to increased lipolysis and thus thermogenesis. Much like UCP1, DNP, and controlled-release mitochondrial protonophore (CRMP) uncouple the ETC from ATP synthesis, increasing thermogenesis.