Studies on fat cell function in human obesity and insulin resistance

Enlarged fat cells, due to excess tri-glyceride (TG) stores with increased basal lipolysis (TG breakdown) and blunted action of the major regulatory hormones of fat cell metabolism (catecholamines and insulin) are hallmarks of common obesity in humans. It is, however, not known whether these aberrations are caused by obesity per se or is a consequence of obesity.

The aim of the present thesis was, firstly, to study the influence of obesity on hormonally induced fat cell metabolism (lipolysis and lipogenesis) and fat cell morphology before and after weight reduction and, secondly, to evaluate putative molecular mechanisms responsible for variations in fat cell metabolism.

In the obese state, hormone stimulated lipolysis was elevated (compared to lean) in women but not in men and basal lipolysis was increased in both genders. After weight loss (to a level still considered obese), basal and stimulated lipolysis in women did not differ from lean controls. However, men did not change their lipolysis in response to weight reduction. Fat cell size was closely related to changes in lipolysis in women but not in men.

A further weight reduction to near normal weight decreased fat cell size and adrenergic regulated lipolysis to values 20-40 % lower than in closely matched controls. In women reaching near normal weight, leptin secretion from adipose tissue and circulating leptin levels were lower in post obese subjects than in matched controls (68% and 54% respectively).

The role of the adipocyte-specific protein perilipin for lipolysis regulation was investigated. Perilipin protein was decreased 50% and basal and stimulated lipolysis increased two to fourfold in the obese state accompanied by increased circulating free fatty acids and glycerol. A gene polymorphism (rs891460) was common and in AA subjects, basal and noradrenaline induced lipolyisis were 50 to 100 % more rapid and perilipin content was reduced by 80%, as compared to GG carriers.

Insulin resistance was present in the obese state but insulin-inhibited lipolysis and lipogenesis were completely normalized after weight loss (compared to matched controls). A strong concentration dependent inverse correlation between adipose TNF-alpha secretion and maximum insulinstimulated glucose transport in adipocytes independent of fat cell volume, age and body mass index was found. Incubation of adipose tissue explants with human recombinant TNF-alpha was also associated with a concentration dependent inhibition of insulin stimulated glucose transport in adipocytes.

In conclusion, evidence exists that the increase in basal and stimulated lipolysis seen in obese women are secondary aberrations due to obesity per se whereas in men increased basal lipolysis might be a primary disturbance or at least more resistant to weight loss. Post-obese women display a hypercellular adipose tissue with small fat cells, low rates of lipolysis and low leptin levels. These might be primary aberrations in part responsible for development of obesity. Adipocyte insulin resistance observed in the obese state is secondary to obesity per se and is associated with increased levels of TNF-alpha secreted from adipose tissue.

List of scientific papers

I. Lofgren P, Hoffstedt J, Ryden M, Thorne A, Holm C, Wahrenberg H, Arner P (2002). Major gender differences in the lipolytic capacity of abdominal subcutaneous fat cells in obesity observed before and after long-term weight reduction. J Clin Endocrinol Metab. 87(2): 764-71.
https://doi.org/10.1210/jc.87.2.764

II. Lofgren P, Andersson I, Adolfsson B, Leijonhufvud BM, Hertel K, Hoffstedt J, Arner P (2005). Long-term prospective and controlled studies demonstrate adipose tissue hypercellularity and relative leptin deficiency in the post-obese state. J Clin Endocrinol Metab. Aug 30: Epub ahead of print.
https://doi.org/10.1210/jc.2005-0596

III. Lofgren P, Hoffstedt J, Naslund E, Wiren E, Arner P (2005). Prospective and controlled studies of insulin and catecholamine action in fat cells of obese women following weight reduction. Diabetologia. [Accepted]
https://doi.org/10.1007/s00125-005-1961-6

IV. Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ, Andersson I, Arner P (2003). Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia. 46(6): 789-97.
https://doi.org/10.1007/s00125-003-1112-x

V. Lofgren P, van Harmelen V, Reynisdottir S, Naslund E, Ryden M, Rossner S, Arner P (2000). Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes. 49(5): 688-92.
https://doi.org/10.2337/diabetes.49.5.688