Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients?

Abstract

An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction (‘sick fat’), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-γ agonists increase the recruitment, proliferation and differentiation of preadipocytes (‘healthy fat’) and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced ‘cross-talk’ with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.

Keywords::

• adiposopathy
• diabetes
• dyslipidemia
• hypertension
• obesity

Notes

*Does not necessarily include adipocyte factors already listed in ‘Transcription factors’ and ‘Extracellular matrix/cytoskeleton factors’ listed in this box, or the “Angiogenesis factors” listed in Box 2, many of which also help regulate adipogenesis. Also, individual adipocyte factors may promote or inhibit adipocyte proliferation or differentiation or both, or have differing effects upon these two processes, which are integral to adipogenesis.

^‡As with other data concerning resistin and metabolic disease, conflicting reports suggest that resistin may enhance or impair adipogenesis. Leukemia inhibitory factor, plasminogen activator inhibitor-1, retinoids also have unclear, and sometimes conflicting data regarding their effects upon adipogenesis. Even the effects of leptin upon adipogenesis are not always consistent in the medical literature

Adipose tissue has many of the same mechanical factors necessary for cellular and tissue functions, and their appropriate activity is no less important to metabolic health than that of other body organs. The normal production, activity, and/or secretion of adipocyte factors are important for normal adipose tissue function. The abnormal production, activity, and/or secretion of adipocyte factors results in dysfunctional fat function – adiposopathy. For example, hypertrophy of adipocytes impairs normal function, and if adipose tissue exceeds its vascular supply, then stimuli such as hypoxia may promote an inflammatory response.