Ectopic Fat-Deposition

The storing of lipids in places other than normal adipose-tissue depots. Ectopic fat deposition (EFD) is a common term for a diverse set of phenomenons, and it can happen in different ways, for different reasons. Histologically it occurs in two forms, with lipids accumulating in the tissue stromal fraction, or inside of parenchymal cells. Commonly there is an overlap between the two.

Stromal EFD occurs through recruitment of fibroadipogenic progenitors that then assumes an adipocyte-like phenotype which primarily serves two purposes, the first one being to support tissue immune- and repair-functions, and the second reason is to provide a buffer-mechanism for maintaining homeostasis under conditions of systemic nutrient overload. This is usually transient and within the scope of normal physiology, but if the immune-response or tissue repair fails, or if a state of systemic nutrient overload is prolonged this can lead to the appearance of persistent or progressing EFD. Similar to stromal EFD, fat-accumulation inside of parenchymal cells can also happen as a result of systemic nutrient overload, when the rate of lipid uptake surpasses the rate of oxidation. However, it is also seen in starvation because of a metabolic shift leading to increased reliance on fat for meeting cellular energy demands. The same thing is observed with endurance athletes. Intracellular EFD has also been shown to be an early sign of hypoxia because decreased oxidative metabolism directs the cell towards a lipogenic phenotype. It can also be a response to low-grade infection, where the cells increase fat uptake to re-organise the composition of membrane-lipids.

Contrary to popular opinion, the connection between ectopic fat and pathology is not mediated by direct lipo-toxicity. In some scenarios increased demands for nutrient handling comes at a physiologic cost, but EFD might also simply be a proxy for changed tissue function and energetics. The presence of different lipids and signal-molecules around or inside the cells may give clues as to what is happening and why. Peroxisome proliferator-activated receptor gamma (PPAR-y) is a master-regulator of lipid storage, and studies using genetic knock-out models have clarified the roll that lipid-accumulation plays in different scenarios.

Supporting Evidence

• Lipids and adipose tissue serves important functions in the response to infection.¹⁾https://iai.asm.org/content/75/3/1066²⁾https://www.ncbi.nlm.nih.gov/pubmed/20358356?dopt=Abstract
• Adipose tissue functions as an immune-barrier outside of parenchymal tissues.³⁾https://rupress.org/jcb/article/208/5/501/54544/The-cell-biology-of-fat-expansionThe-cell-biology
• Obesity is protective in sepsis, perhaps confounded by IR.⁴⁾https://bmjopen.bmj.com/content/8/9/e021979⁵⁾http://www.jneurosci.org/content/30/17/6036⁶⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579888/⁷⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765286/⁸⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533197/⁹⁾https://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1360-z
• Periarticular fat-pads express increased amounts of inflammatory mediators in OA and RA (RA>OA).¹⁰⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462341/¹¹⁾https://www.nature.com/articles/nrrheum.2017.145
• Lipodystrophic adipose tissue have a diminished ability to mount an immune-response.¹²⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806777/ 
• Evidence of synergy between adipocytes and macrophages in inflammation.¹³⁾https://www.sciencedaily.com/releases/2019/02/190228154844.htm¹⁴⁾https://www.ncbi.nlm.nih.gov/pubmed/29804185¹⁵⁾https://www.ncbi.nlm.nih.gov/pubmed/24204798¹⁶⁾https://science.sciencemag.org/content/363/6430/931.summary¹⁷⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579605/¹⁸⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563356/¹⁹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586118/²⁰⁾https://www.ncbi.nlm.nih.gov/pubmed/24339422
• Blocking PPAR-y in macrophages affects genes related to inflammation rather than fat-metabolism.²¹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142832/
• Lysosomal degradation of lipids in macrophages provide a buffer-mechanism to nutrient overload.²²⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042402/
• Blocking perimuscular fat-accumulation is detrimental to the repair-response to injury.²³⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073847/
• Macrophages exposed to hypoxia up-regulates receptors and enzymes for VLDL-uptake and -oxidation respectively.²⁴⁾https://www.jimmunol.org/content/jimmunol/175/10/6257.full.pdf
• Three days of immobilisation causes an increase in muscular EFD.²⁵⁾https://www.ncbi.nlm.nih.gov/pubmed/29248005
• Metabolic and mechanical load shown to be competing stimuli in tenocytes in vitro.²⁶⁾https://www.ncbi.nlm.nih.gov/pubmed/29283422
• Extra-parenchymal muscular adipose tissue is associated with systemic insulin resistance.²⁷⁾https://www.ncbi.nlm.nih.gov/pubmed/28555462.
• Presence of different lipid-intermediates rather than total intracellular fat mediates connection with IR.²⁸⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997379/
• Lipid-intermediates that are associated with IR serves autophagic and anti-septic functions.²⁹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960371/³⁰⁾https://www.sciencedirect.com/science/article/pii/S0014579315005827

Association with Disease

• Associated with loss of function in skeletal muscle.³¹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910392/
• Small association between paraspinal EFD and NSLBP.³²⁾http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187765
• EFD in paraspinal muscles associated with lower odds of return to sport in athletes with LBP.³³⁾https://www.ncbi.nlm.nih.gov/pubmed/28817410
• Fat-accumulation around the vertebral end-plates and paraspinal muscles is associated with DDD.³⁴⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073831/³⁵⁾https://www.ncbi.nlm.nih.gov/pubmed/29379999³⁶⁾https://josr-online.biomedcentral.com/articles/10.1186/s13018-019-1355-y
• Increased fatty-infiltration of paraspinal muscles, side-specific to lumbar DH.³⁷⁾https://www.thespinejournalonline.com/article/S1529-9430(20)30142-X/fulltext?dgcid=raven_jbs_aip_email
• Epidural EFD can give worse DH-symptoms by reducing the epidural space.³⁸⁾https://doi.org/10.1016/j.spinee.2017.07.177
• Change in periarticular fat-mass is associated with cartilage-deterioration in OA.³⁹⁾https://www.ncbi.nlm.nih.gov/pubmed/30537040
• Synovial lipomatosis might be an epiphenomenon in some cases of OA.⁴⁰⁾https://www.ncbi.nlm.nih.gov/pubmed/31080194⁴¹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249723/⁴²⁾https://www.sciencedirect.com/science/article/pii/S221433001520140X
• Associated with impaired regenerative capacity in bone- and muscle-tissue.⁴³⁾https://www.nature.com/articles/cddis2015198⁴⁴⁾https://www.ncbi.nlm.nih.gov/pubmed/28330582⁴⁵⁾https://www.ncbi.nlm.nih.gov/pubmed/27493874,
• Increased EFD in neck-muscles of Whiplash-patients.⁴⁶⁾https://www.ncbi.nlm.nih.gov/pubmed/25785961
• High levels of muscular EFD is associated with a blunted adaptive response to load.⁴⁷⁾https://link.springer.com/article/10.1007/s12603-012-0377-5
• EFD under the thoracolumbar fascia can herniate and cause pain.⁴⁸⁾https://www.ncbi.nlm.nih.gov/pubmed/25794233
• Muscular EFD can have direct biomechanical consequences for the tissue.⁴⁹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535407/
• Paraspinal muscle EFD is a common finding in NSLBP and might be a precursor to spinal deformity.⁵⁰⁾https://www.ncbi.nlm.nih.gov/pubmed/28291378