Of the nutrient energy intake of an individual organism, a small portion is lost in the feces and urine; a portion is used for physiological needs, such as growth, pregnancy, or lactation; a variable portion is used in physical activity; while the majority of ingested calories is used for metabolic processes or is lost in the production of heat. Based on the function and tissues of heat production, thermogenesis can be further classified into six categories. Adaptive thermogenesis is defined as regulated heat production in response to environmental temperature or diet. There are three subcategories of adaptive thermogenesis. Cold exposure induces shivering thermogenesis in skeletal muscle, and non-shivering thermogenesis in brown fat. While current evidence does not indicate a role of muscle in non-shivering thermogenesis, indirect evidence suggests that such mechanisms may exist. Overfeeding triggers diet-induced thermogenesis; this is also a function of brown fat.

(A) Regulated increases in thermogenesis occur in brown adipocytes with the stimulation of beta adrenergic receptors (βAR), starting a signal transduction cascade that produces cAMP and activates PKA, which then activates multiple enzymes responsible for converting the catabolic endproducts of macronutrients (carbohydrates (CHO), fats (TAG), and proteins) into mitochondrial fuel. The TCA cycle generates protons (H⁺) and electrons (e) that are carried by NADH and FADH to the ETC where the protons are transported to the mitochondrial intermembrane space, generating an electrochemical gradient (ΔµH⁺) that is used by the F₀/F₁-ATPase to convert that potential energy into the phosphoanhydride bonds in ATP. Meanwhile, the electrons are transported in successive steps through the ETC complexes until they are received by O₂ to make H₂O. The highly reactive electrons also lead to ROS, which can cause significant cellular damage. The TCA also produces CO₂ as a byproduct. The respiratory quotient (RQ) is the ratio of CO₂ produced / O₂ consumed and typically ranges between 0.7 for fats and 1.0 for carbohydrates. Thus, RQ can help identify the mitochondrial fuel source.
(B) Multiple tissues, including muscle, generate heat via uncoupled processes such as leakage of ions (H⁺, Na⁺, K⁺, Ca²⁺) through channels back down their electrochemical gradients. Shown here is the ubiquitous Na/K ATPase releasing heat energy and Na⁺ and K⁺ leaking back to perpetuate this “futile” cycle.
(C) Myocytes can also increase thermogenesis through a series of uncoupled reactions. Neurotransmitter-mediated opening of (1) cell-surface Na⁺ channels leads to (2) release of Ca²⁺ into the cytoplasm from sources both outside the cell and (3) the sarcoplasmic reticulum via the ryanodine receptor (RyR). Dysfunction of this receptor leading to uncontrolled Ca²⁺ release underlies the thermogenesis in malignant hyperthermia 44. Ca²⁺ leads to heat generation from (4) ATP hydrolysis during both muscle relaxation and actinomyosin cross-bridge cycling during sustained contraction. Additional heat energy is released (5) when Ca²⁺ ions are pumped back into the sarcoplasmic reticulum by the sarcoplasmic reticulum calcium ATPases (Ca-ATPase).
(D) Triglyceride/fatty acid cycling is an example of a “futile” cycle involving muscle and adipose tissue in which esterification of triglycerides is followed by hydrolysis, leading to increased heat expenditure in processes as diverse as burn injuries, cancer cachexia, and after exercise.
Abbreviations: βAR, beta adrenergic receptors; Ca-ATPase, C, cytochrome C; CHO, carbohydrates; complex I, NADH–ubiquinone oxidoreductase; complex II, succinate–ubiquinone oxidoreductase; complex III, ubiquinone–cytochrome-c oxidoreductase; complex IV, cytochrome-c oxidase; ETC, electron transport chain; FFA, free fatty acids; PKA, protein kinase A; Q, ubiquinone; ROS, reactive oxygen species; RyR, Ryanodine receptor ; TAG, triacylglycerols; TCA, tricarboxylic acid cycle; UCP1, uncoupling protein 1

In this model, we propose that there are distinct progenitors giving rise to the preformed versus systemic brown adipocytes. While the myf5-expressing progenitors give rise to skeletal muscle and interscapular brown fat 92, a distinct myf5-negative tissue resident progenitor serves as the common precursor for white adipocyte and the systemic brown adipocyte. The development of a fully functional brown adipocyte can be divided into three phases. The “commitment phase” is when multipotent mesenchymal stem cells become committed to brown adipocyte lineage in response to developmental cues, such as BMPs and FGFs. The “differentiation phase” is committed brown preadipocytes undergo a series of morphological and enzymatic changes to become rounded lipid-containing fat cells. This process is regulated by a number of growth factors and hormones and involved activation of transcriptional cascade. The “activation phase” refers as the stage when the maximal thermogenic capacity in matured brown adipocytes is turned on by hormonal or sympathetic stimulations.

Based on the current knowledge of bioenergetics, four potential therapeutic approaches could be envisioned: (1) increasing brown fat differentiation from progenitor cells, (2) activating brown fat thermogenesis, (3) promoting skeletal muscle thermogenesis: or (4) increasing general mitochondrial uncoupling. For skeletal muscle, there are three types of thermogenesis: exercise-induced thermogenesis, non-exercise activity thermogenesis, and cold-induced shivering thermogenesis. Thus, therapeutic interventions that mimic these mechanisms could potentially increase muscle’s thermogenic capacity and counteract obesity. This is especially beneficial to individuals with physical limitations in exercising or those who are genetically predisposed to obesity. All of these approaches can be applied in the conventional pharmaceutical approaches of developing drugs and/or using natural food components targeting key pathways of cellular bioenergetics. Alternatively, there is a cell-based therapy where progenitors are isolated from patients during liposuction or biopsy, manipulated ex vivo by treating them with factors that promote BAT differentiation or transfecting them with genes specifying BAT differentiation, then transplanted these cells back into the same individual to generate a functional brown fat to help dissipate excess energy.