Cover Story Current Issue

Obesity represents a complex medical and behavioural problem which is insufficiently managed by current treatment interventions. Over the past decades, it has become increasing clear that the brain plays a fundamental role in regulating energy balance and body weight homeostasis. Central control of eating and energy balance is determined by a rich interplay of humoral, neuronal and molecular mechanisms.

Henrik H. Hansen, Johanna Perens, Urmas Roostalu, Jacob Lercke Skytte, ... Jacob Hecksher-Sørensen

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Current Issue

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Leigh Goedeke, Gerald I. Shulman

Background

Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases.

Scope of review

In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis(NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic.

Major conclusions

Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Leigh Goedeke, Gerald I. Shulman

Background

Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases.

Scope of review

In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis(NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic.

Major conclusions

Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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The 8th Helmholtz Diabetes Conference

The 8th Helmholtz Diabetes Conference will take place virtually from May 10th-12th. This year, the conference will focus on the genetic and epigenetic mechanisms involved in the development of diabetes.

For more information and to register, click here.