Targeting energy expenditure via fuel switching and beyond

Abstract

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an overnutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

“…For example, intermittent fasting and exercise can protect neurons against dysfunction and degeneration in animal models of Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke [5–11]. Conversely, individuals who are sedentary, possess the over-nourished metabolic phenotype and are not intellectually engaged (the so-called ‘couch potato’ lifestyle) are at increased risk of AD and stroke and a host of other comorbidities [4, 12, 13]. …”

“…The first UCP discovered, UCP1, is expressed in brown fat cells where its function is to cause heat production in mammals living in cold environments [32]. However, humans have ~50-fold less brown fat than rodents, and UCP1 therefore plays a negligible role in thermogenesis in human [13]. However the UCP1 homologues, UCP2, UCP3, UCP4 and UCP5 (BMCP1), are more widely expressed and have roles in the mitochondria related to cellular stress adaptation [33].…”

“…It is therefore widely understood that most drugs and many natural products exhibit a ‘therapeutic window’ for clinical efficacy that, if exceeded, can result in adverse events, including death. Here we summarize the human experience with DNP, the notorious weight loss agent from the 1930’s that acts as a protonophore that allows H + to leak across the inner mitochondrial membrane, and is therefore a “mitochondrial uncoupler” [13]. …”

“…Indeed, the target of chemical uncouplers such as DNP is not a protein, but is instead the mitochondrial membrane where they transfer protons to the matrix [13]. Although DNP’s initial uncoupling action is non-genomic, several prominent signaling cascades involved in adaptive neuroplasticity and stress resistance are activated including those involving calcium and cyclic AMP, and downstream kinases and transcription factors (Figure 2) [56, 97].…”

Of mice and men: novel insights regarding constitutive and recruitable brown adipocytes

“…BAT mass in rodents is~0.4-1% of body weight (Townsend and Tseng, unpublished dissection data, and Geisler 108 ), whereas in humans it is estimated at~0.02% of body weight, 108 and thus humans have relatively less BAT than rodents. Small mammals may utilize BAT to oxidize up to 90% of daily fuel intake; BAT has been shown to account for the majority uptake of ingested glucose and the most cold-stimulated triglyceride clearance.…”