Team:Hong Kong HKUST/modelling

Worldwide obesity has nearly doubled since 1980, while in 2008, more than 1.4 billion adults, 20 and older, were overweight. In particular, many low- and middle-income countries face “double burden” of under-nutrition and obesity. Rates of malnutrition is much higher in low income countries, while there is a greater exposure to high-sugar, high-fat, high-salt foods which are low in cost and nutrients. Such dietary patterns result in low levels of physical strength and sharp increase in childhood obesity with under-nutrition existing side-by-side.

2. In obesity, fatty acids delivered to liver may outpace fatty acid oxidation in hepatocytes, resulting in triglyceride accumulation. Obesity leads to health hazards, including cardiovascular disease - mainly heart disease and stroke, diabetes, musculoskeletal disorders, especially osteoarthritis – a highly disabling degenerative disease of the joints, and cancers, such as endometrial, breast and colon cancers. Combined: http://www.healthcentral.com/common/images/1/19473_13187_5.jpg Cardiovascular: Obesity and other health conditions associated with obesity, including hypertension, insulin resistance, diabetes and hyperlipidemia, are risk factors of cardiovascular disease. http://www.beltina.org/health-dictionary/obesity-cardiovascular-disease-bmi-table.html Diabetes: Patients with type 2 diabetes are insulin resistant, in which high levels of blood fats, cholesterol and triglyceride levels inhibit cells from absorbing blood sugar needed. http://www.bubblews.com/news/560642-cause-of-type-2-diabetes Musculoskeletal disorders: Those with a body mass index (BMI) greater than 26.4 had rate of osteoarthritis of the knees 6 times greater than those with a body mass index of less than 23.4. (Ref. J. Rheumatol. 20 (2) 331-5) http://pharmaworlds.com/obesity-a-growing-burden-for-physicians-and-patients/

The fundamental cause of obesity is an energy imbalance between calories consumed and expended. To increase expenditure of fatty acids (calories), HKUST 2013 Team aims to introduce glyoxylate shunt as an artificial futile cycle in HepG2 cell.

Part 1 Sense Fatty Acids: We investigated four different sensing mechanisms using: 1) fatty acid metabolism regulator protein (FadR), 2) peroxisome proliferator-activated receptor-alpha (PPAR-alpha) 3) liver- fatty acid binding protein (FABP1) and 4) binding immunoglobulin protein, HSP5 or glucose regulated protein (GRP78). The four sensing mechanisms were measured and compared.

Part 2 Introduce Glyoxylate Shunt: We introduced two key enzymes of glyoxylate cycle: isocitrate lyase (ACEA) and malate synthase (ACEB), which allow plants and bacteria to use fatty acids as a substrate for gluconeogenesis. Here, the amount of fatty acids was measured to compare fatty acids uptake rates of cells expressing glyoxylate shunt.

Integration of Parts: The integration of sensing mechanism and glyoxylate shunt allows inducible glyoxylate shunt, in which the high levels of free fatty acids in the medium increase fatty acid uptake rate of glyoxylate shunt.

Although the problem of malnutrition may remain unsolved, the inducible glyoxylate shunt introduced to mammalian cell increases consumption of fatty acids, lowering the risk of excessive fat accumulation that presents risk to health.