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MSCA-TOPP-UT-Toppfinansiering av MSCA utgående kandidater

Topfinancing: Exploring the underlying mechanisms of partial leptin reduction towards a non-invasive obesity therapy

Alternative title: Toppfinansiering: Kartlegging av de underliggende mekanismene bak delvis leptin reduksjon mot en ikke-invasiv fedmeterapi

Awarded: NOK 0.58 mill.

The overall goal of this proposal is to develop a new anti-obesity therapy. The project idea is based on a hormone called leptin, which is important for regulating the energy balance in our body. An extensive amount of effort has been put into understanding how manipulation of leptin levels can reduce body weight, but until now the results have been disappointing. However, Scherer et al recently published a new strategy in which leptin levels are partially reduced in the blood stream. This degree of depletion causes weight loss and reduced food intake as well as anti-diabetic effects. The physiological benefits of partial leptin reduction have thus already been demonstrated. The overall goal of this proposal is therefore to understand what actually happens on a cellular level upon partial leptin reduction. The effects will be examined using both antibodies and advanced mouse genetics and we will determine the cellular signaling events using new technologies on both protein and gene level. In addition, we will determine whether leptin lowering can improve the effects of existing weight loss approaches and whether anti-diabetic interventions rely on leptin lowering independent of weight loss.

Leptin regulates energy balance by functioning as a satiety signal. When identified 26 years ago, expectations were high that leptin therapies could be used for the treatment of obesity. In contrast to the successful use of leptin for treatment of individuals with lipodystrophy and complete leptin deficiency, pharmacological approaches using leptin therapy for the treatment of diet-induced obesity have been widely unsuccessful. Injecting recombinant leptin in the context of obesity, associated with elevated leptin levels, remains ineffective as central neurons become leptin resistant. Interestingly, Scherer et al. recently published a series of findings that encourages for a conceptual shift. They reported that a partial reduction of circulating leptin levels in the obese state prompts an unexpected systemic response resulting in weight loss, reduced food intake, improved glucose and insulin tolerance and increased energy expenditure - all consistent with leptin re-sensitization in central neurons. The systemic physiological benefits of partial leptin reduction have already been demonstrated. The overall goal of this proposal is therefore to determine the underlying molecular mechanisms that are induced by leptin reduction and trigger leptin re-sensitization. Understanding of these conceptual steps should lead us to explore partial leptin reduction as a viable avenue for anti-obesity and anti-diabetic therapy in the near future. We aim to determine the peripheral effects of leptin reduction using neutralizing leptin antibodies and advanced mouse genetics. Moreover, we will determine downstream signaling events that are affected in peripheral tissues upon leptin depletion using imaging mass cytometry and transcriptional regulation by single cell RNAseq. Finally, we will also determine whether leptin lowering offers synergistic effects with existing weight loss approaches and whether anti-diabetic interventions rely on leptin lowering independent of weight loss.

Funding scheme:

MSCA-TOPP-UT-Toppfinansiering av MSCA utgående kandidater

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