high-fat overfeeding, hepatokines and appetite regulation

Conditions: Insulin Resistance; Type2 Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Obesity

Summary: the present study will investigate the effect of high-fat overfeeding on a group of liver-secreted proteins linked to worsened blood sugar control, as well as proteins involved in appetite control. participants will consume both a high-fat diet, consisting of 50% extra calories above their daily required intake, and a control diet, consisting of their normal 'habitual' diet, with each diet lasting seven days. the diets will be undertaken in a randomised order, with a period of three weeks separating the two diets. blood samples will be taken before and after each diet to measure blood sugar control. further blood samples will also be taken 24 hours and 72 hours into each diet to see how levels of the liver and appetite-regulating proteins change over the course of the seven days. it is expected that blood sugar control will be worsened by the high-fat diet and this will be accompanied by increases in levels of the liver-secreted proteins and an impaired release of the appetite-regulating proteins into the blood.

in recent years, researchers have identified a number of liver-secreted proteins, termed "hepatokines", which are thought to play an important role in inter-organ crosstalk between the liver and other metabolically active tissues such as skeletal muscle and adipose tissue. specifically, previous studies have demonstrated that hepatokines contribute to whole body glucose and lipid homeostasis through acting in an endocrine-like fashion. understanding how circulating concentrations of these hepatokines can be manipulated in humans is essential, as impaired blood glucose and lipid control is a key feature of metabolic diseases, such as type 2 diabetes and non-alcoholic fatty liver disease. previous research at loughborough university has found that acute high-fat overfeeding for up to seven days can impair glycaemic control; however, the exact mechanisms responsible for these detrimental changes are not fully understood. based upon previous evidence that hepatokine production is nutritionally modulated, the investigators believe that changes in hepatokine production may play a role in the detrimental metabolic effects seen following short-term, high-fat overfeeding which has implications for long-term metabolic health. appetite regulation is also thought to play a role in the pathophysiology of obesity and insulin resistance, as the impaired secretion of several appetite regulatory hormones in both fasting and postprandial conditions has been observed in obesity, which is characterised by an chronic excessive energy intake. therefore, the investigators are also interested to examine the appetite regulatory hormone response to short-term, high-fat overfeeding. the present study is a randomised, controlled, crossover study in which twelve recreationally active, healthy males will consume both a hypercaloric, high-fat diet (consisting of 50% extra energy above the daily requirement, 65% of which is fat) and a control diet (the participants' habitual diet) in a randomised fashion. a three-week washout period will separate the two diets in order to remove any lasting effects confounding the subsequent diet. following a prescreening session in which anthropometric data will be collected, participants will commence their first dietary condition. an oral glucose tolerance test will be performed before and after the two diets to measure changes in glycaemic control/whole body insulin sensitivity. further blood samples will be taken 24 hours and 72 hours after commencing the diets in order to observe the time course of any changes in circulating hepatokine and appetite hormone concentrations. physical activity will also be monitored for the duration of the two dietary conditions to ensure that habitual physical activity levels are maintained.

Eligibility criteria:
inclusion criteria: * recreationally active - ≤ 2 structured exercise sessions per week * bmi between 18.5 - 27.9 kg/m2 * body fat percentage \< 20% * metabolically healthy - no known cardiovascular or metabolic disease such as diabetes, respiratory or heart disease. * non-smoker * weight stable in the past 6 months * normal fasting blood glucose levels (3.6 - 5.5 mmol/l) exclusion criteria: * contraindications to exercise * needle phobia

Keywords: hepatokines high fat diet glycaemic control fibroblast growth factor 21 leukocyte cell-derived chemotaxin 2 fetuin-a appetite ghrelin peptide yy