Obesity and Lipodystrophy

What is obesity?

Obesity is defined by increased body size, specifically having excess adipose tissue (fat tissue). Under normal conditions, adipose tissue actively stores and releases energy in the form of triglycerides and regulates food intake, energy expenditure, and fuel metabolism through its secretory products called adipokines. However, when there is adipose tissue dysfunction resulting from abnormal adipokine secretion and other abnormalities, it can lead to obesity. There are several risk factors for obesity, including lack of physical activity, unhealthy eating behaviors (i.e., consuming more calories than you burn, high consumption of processed food with saturated fats or added sugars), lack of sleep, high amounts of stress, and certain health conditions such as polycystic ovary syndrome and medications such as antidepressants. Genetics also may play a role; reportedly, there are 15 genes associated with obesity that may predispose individuals to developing obesity. Obesity also increases the risk of many other comorbidities, including heart disease, type 2 diabetes, hypertension, dyslipidemia, liver steatosis, sleep apnea, and certain cancers. Obesity, in general, is defined using criteria such as body mass index (BMI) or waist circumference. Excess fat in the subcutaneous truncal and intra-abdominal regions can determine the prevalence and severity of insulin resistance and its associated complications.

What is lipodystrophy?

Lipodystrophies are a rare heterogenous group of acquired or congenital (genetic) metabolic disorders

characterized by general, local, or partial loss of adipose tissue and frequently accompanied by adipose tissue dysfunction. Different types of lipodystrophies are generally classified as congenital generalized lipodystrophy (CGL) or familial partial lipodystrophy (FPLD), and each varies in onset and presentation. 

• Congenital Generalized Lipodystrophy is an inherited condition, and infants begin losing weight a few weeks after birth. Generalized lipodystrophy, the most severe form, has almost no subcutaneous fat or adipose tissue, so individuals' arms and legs appear thin. 

• Familial Partial Lipodystrophy is also inherited, where individuals begin to lose fat tissue during puberty. Fat loss can also occur from their arms and legs and may store fat around the face, neck, and abdomen.

• Acquired Generalized Lipodystrophy, also known as Lawrence syndrome, develops during adolescence and has a similar presentation to CGL. The genetic cause is currently unknown. 

• Acquired Partial Lipodystrophy, also known as Barraquer-Simons syndrome, develops after birth, and loss of fat usually occurs around the face, neck, and upper extremities and does not usually affect the lower limbs. 

• HIV-related Lipodystrophy is a rare form that occurs in some people who take antiretroviral medication to treat HIV; this does not reverse if the person stops taking antiretroviral medication. 

• Localized Lipodystrophy usually affects people who receive repeated daily injections, such as regular insulin injections, to manage diabetes. Fat loss only occurs at the injection site, creating small dimples or "crater-like shapes." 

What are the clinical similarities?

Although obesity and lipodystrophies may present with different clinical features, there are some biological similarities. Individuals with either condition experience a limitation in the storage of triglycerides in adipose tissue; during obesity, adipose tissue has reached its limit in fat storage, and in lipodystrophy, there is little to no fat storage. Thus, this results in diverting triglycerides to abnormal sites (liver, skeletal muscle, pancreas) for fat storage, leading to hepatic and peripheral insulin resistance and related conditions such as hypertriglyceridemia and hepatic steatosis. Also, triglycerides are reactive molecules, and these organs were not designed to handle fat storage. If poorly controlled, these metabolic disorders progress to the most severe comorbidities associated with obesity and lipodystrophy, such as acute pancreatitis, hepatic cirrhosis/carcinoma, renal failure, and cardiovascular disease.

What are potential treatments?

Diet and Exercise: For both conditions, a reduction of energy intake, specifically dietary triglycerides or dietary fat, to avoid ectopic triglyceride deposition in the liver, skeletal muscles, and other vulnerable tissues is recommended to help mitigate metabolic complications of both obesity and lipodystrophy. However, patients with generalized lipodystrophies, particularly children, have voracious appetites that are difficult to control, and children require energy for growth and development. Dieting, therefore, should be monitored, but must also allow for adequate growth in young patients. Also, increasing energy expenditure with daily physical activity, particularly aerobic exercise, can improve metabolic complications in both obesity and lipodystrophy. 

Medication: Incretin hormone called GLP-1 (glucagon-like peptide 1) is a peptide hormone made in endocrine cells in the gut in response to eating, and its signaling is across multiple organs. GLP-1 tells the body it has enough food, and it's a natural feedback mechanism to stop eating and turn down the desire to eat more food. It lowers blood glucose through stimulation of insulin secretion and suppression of glucagon secretion, ultimately enhancing satiety. The GLP-1 analogs are synthetic forms of this hormone that act longer, approximately up to a week. Natural incretin acts for 5 minutes. These drugs address the obesity problem from the energy intake side. In lipodystrophy, research has shown that GLP-1 agonists improve metabolic disease (insulin resistance and liver steatosis) in a pre-clinical lipodystrophy model. Leptin replacement therapy by metreleptin, a recombinant leptin analog, has been approved to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy. Leptin is produced by adipose tissue and assists in regulating central satiety signals or feelings of fullness and energy expenditure. Depending on the type of lipodystrophy an individual has, they may have little to no leptin production. Unfortunately, leptin replacement therapy does not have the same metabolic protection in individuals with obesity.  

Takeaways

Adipose tissue plays an essential role in the body of all living mammals. It preserves nutrients in the form of fat for future use by expanding and multiplying in response to nutritional energy intake as a survival mechanism. Although different in origin, both obesity and lipodystrophies experience abnormal adipose tissue dysfunction due to a limitation in fat storage. Lipodystrophy has gained less attention than obesity, mainly because of its lower prevalence since forms of genetic lipodystrophies are quite rare. However, research into acquired and genetic lipodystrophy is becoming increasingly significant, mainly because the incidence of genetic lipodystrophy is rising. Research studies on lipodystrophies may provide additional knowledge into the biology of adipocytes and further our understanding and identification of mechanisms leading to obesity and developing potential treatments to address these conditions. 

Written by Krystal Roggerson, PhD

Edited by Helen Lu

References 

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