Promoting metabolic inefficiency for metabolic disease

Abstract

Recent advances in pharmacotherapies that promote appetite suppression have shown remarkable weight loss. Therapies targeting energy expenditure lag behind, and as such none have yet been identified to be safe and efficacious for sustaining negative energy balance toward weight loss. Multiple energy dissipating pathways have been identified in adipose tissue and muscle. The molecular effectors of some of these pathways have been identified, but much is still left to be learned about their regulation. Understanding the molecular underpinnings of metabolic inefficiency in adipose tissue and muscle is required if these pathways are to be therapeutically targeted in the context of obesity and obesity-accelerated diseases.

Keywords: Human metabolism.

Figure 1

Different modes of thermogenesis Cartoon of thermogenesis by (A), proton re-entry independently of ATP synthesis (H+ leak) or (B), promoting substrate oxidation by ATP turnover (ATP sink).

Figure 2

Thermogenesis by uncoupling protein 1 (UCP1) and the futile creatine cycle Complexes I, III, and IV of the electron transport chain extrude protons (H⁺) from the matrix to the intermembrane space to generate an electrochemical gradient across the mitochondrial inner membrane. Thermogenesis mediated by proton (H⁺) leak via UCP1 or by ATP turnover via the futile creatine cycle occurs because of H⁺ re-entry back to the matrix which relieves the thermodynamic backpressure on the electron transport chain, which promotes substrate oxidation, respiration, and thermogenesis. CKB, Creatine kinase B; TNAP, Tissue non-specific alkaline phosphatase, UCP1, uncoupling protein 1, Cr, creatine; PCr, phosphocreatine; Pi, inorganic phosphate.

Figure 3

Thermogenesis by UCP1 and the futile calcium cycle Thermogenesis mediated by proton (H⁺) leak via UCP1 or by ATP turnover via the futile calcium cycle occurs because of H⁺ re-entry back to the matrix which relieves the thermodynamic backpressure on the electron transport chain, which promotes substrate oxidation, respiration, and thermogenesis. ER, endoplasmic reticulum; SERCA2b, sarcoplasmic and endoplasmic reticulum calcium ATPase 2b; RYR2, Ryanodine receptor 2, UCP1, uncoupling protein 1, Ca²⁺, calcium.

Figure 4

Thermogenesis futile lipid cycle Thermogenesis mediated by ATP turnover via the futile lipid cycle occurs because of H⁺ re-entry back to the matrix which relieves the thermodynamic backpressure on the electron transport chain, which promotes substrate oxidation, respiration, and thermogenesis. This cycle has been reported to occur primarily in white adipocytes, but has been shown to also occur in brown adipocytes that genetically lack Ucp1 or where the mitochondrial pyruvate carrier has been pharmacologically inhibited.

Figure 5

Thermogenesis by futile calcium cycling in muscle Thermogenesis mediated by ATP turnover via muscle-based futile calcium cycling occurs because of H⁺ re-entry back to the matrix which relieves the thermodynamic backpressure on the electron transport chain, which promotes substrate oxidation, respiration, and thermogenesis. SR, sarcoplasmic reticulum; SERCA, sarcoplasmic and endoplasmic reticulum calcium ATPase; RYR1, Ryanodine receptor 1; SLN, Sarcolipin; NNAT, Neuronatin; Ca²⁺, calcium.