Globally, there is a growing population of people who are overweight or obese, with 1 in 4 adults in the UK estimated to be affected by obesity. The scale alongside the rise in obesity-related comorbidities, has fuelled the medical, pharmaceutical and research community’s interest in obesity as a disease with life threatening implications.

Due to its role in metabolism, adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a molecular target of interest to the pharmaceutical industry for the treatment of metabolic diseases, such as diet-induced obesity. AMPK is a protein that regulates energy balance, often referred to as the guardian of cellular energy metabolism.

In a study, published in Nature Metabolism on 25 February researchers from the Cellular Stress group at the LMS in collaboration with AstraZeneca found that genetic activation of a specific form of AMPK resulted in protection against diet-induced obesity due to an increase in whole-body energy expenditure.

Reduction in weight and fat accumulation
Researchers observed decreased weight gain and fat accumulation in their AMPK activated model compared to control when fed a high fat diet. The physiological findings suggested that this was due to an increase in diet-induced thermogenesis (production of heat).

The increase in whole-body energy expenditure is partially due to a change in the cellular structure in the subcutaneous white fat tissue. Researchers observed that cells in the subcutaneous white fat had a high number of mitochondria and tested positive for a number of well-known skeletal muscle gene and protein biomarkers.

Functionally, fat and muscle cells are quite different. Fat cells store energy in the form of lipid droplets, whereas muscle cells use up energy through contraction and relaxation to produce force and movement. However, brown fat cells share similarities with both cell types. Due to the high number of mitochondria within brown fat cells they are able to use up stored energy reserves through the production of heat.

Exploring the mechanism of thermogenesis
The researchers proceeded to investigate the mechanism that had led to the development of ‘brown fat’ and skeletal muscle characteristics in the subcutaneous white fat. One avenue of investigation was UCP-1 (uncoupling protein-1), a protein found in the mitochondria of brown fat cells, but not usually found in white fat cells. Numerous studies have revealed that UCP-1 plays a key role in the generation of heat in brown fat cells rather than ATP production, the usual energy currency of a cell. But the lack of UCP-1 expression detected in the study, led the researchers to believe that the effects were independent of UCP-1.

These observations led the researchers to conclude that the genetic activation of AMPK does not have a significant effect on brown fat tissue nor that brown fat mediated thermogenesis plays a major role in the protection against diet-induced obesity observed in their model.

Looks like fat, acts like muscle
To investigate the mechanism of UCP-1 independent thermogenesis the researchers conducted a genetic screen of the subcutaneous white fat tissue from their model. One of the key findings from this screening was the marked increase in expression of a number of well-known skeletal muscle genes.

The screening and subsequent immunoblotting confirmed that there were significant increases in ryanodine receptor 1(Ryr1) and sarcoplasmic/ endoplasmic reticulum Ca²⁺– ATPase 1 (Serca1) protein expression. This supported a recent study which reported that Serca2b and Ryr2 are involved in Ca²⁺cycling-dependent thermogenesis in beige fat tissue. (Ikeda et al. Nat. Med. 2017) The use of Ca²⁺transport to produce heat without muscle contraction has also been revealed in studies of fish where this specialised function of muscle is referred to as heater organs. (Block et al. J. Cell. Biol. 1994)

First author of the study, Alice Pollard, now research associate in the Cellular Stress group was a CASE PhD student working on this project with collaborators at AstraZeneca. Discussing the key findings of research says:

“Research in this field has focused primarily on UCP-based thermogenesis to enhance energy expenditure for the treatment of obesity and metabolic disorders, with limited therapeutic benefit. The existence of alternative thermogenic pathways, whilst well-described in muscle, are underappreciated in brown adipose (fat) tissue, despite a common cell lineage. To observe similar, functional skeletal muscle-based endothermy in brown-like white adipose tissue is extremely encouraging for the field of metabolism, with AMPK providing an attractive, previously unidentified target for its induction.”

David Carling, Head of the Cellular Stress Group, discusses the next steps for this study:

“One of the key challenges for us now is to identify the cells responsible for the non-UCP1 mediated thermogenesis and to characterise the molecular mechanisms controlling their growth. These cells may provide a new therapeutic opportunity for increasing energy expenditure, leading to sustainable weight loss.”

Jon Read, Principal Scientist, Discovery Sciences at AstraZeneca, commented:

“The findings of this research shed light on the biology of AMPK – the central regulator of energy regulation. In the study, activation of AMPK results in the development of unique cells in fat tissue which develop to become more muscle like in both gene expression and phenotype and importantly show increased energy expenditure. We believe this is an important step in creating understanding that could lead to treatments of obesity-related diseases in the future.”

This research builds upon previous work from the Cellular Stress group, which showed that liver specific activation of γ1 subunit of AMPK protected against lipid accumulation in the liver.

The findings from the current study indicate that AMPK activation specifically in white fat tissue may have therapeutic potential for the treatment of diet-induced obesity.

AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue was published in Nature Metabolism on 25 February. Read the article here.

 

References
Ikeda, K. et al. UCP1-independent signalling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017).

Block, B. A., O’Brien, J. & Meissner, G. Characterization of the sarcoplasmic reticulum proteins in the thermogenic muscles of fish. J. Cell. Biol. 127, 1275–1287 (1994)