Lipid Metabolism and Nutrient Partitioning Strategies

Abstract

The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task.

Effects of feed restriction during organogenesis on embryo-fetal development in rabbit

“…Understanding the relationship between maternal body weight gain during pregnancy and prenatal development in non‐clinical studies becomes even more important when the pharmacology of the drug under evaluation is intended to promote weight loss. Strategies being explored to promote weight loss include appetite suppression, inhibition of nutrient absorption and alterations in metabolic function (Appolinario et al, 2004; Clapham, 2004; Jandacek and Woods, 2004; Morris et al, 2004; Small and Bloom, 2004). Regardless of the mechanism of action, many of these compounds will cause weight loss in non‐clinical species.…”

The effects of feed restriction during organogenesis on embryo-fetal development in the rat

“…Elevated doses in non‐clinical safety studies are intended to address “off‐target” toxicities or the effects of exaggerated pharmacology, and when the compound is intended to produce weight loss, separating the weight loss due to off‐target toxicity from that due to the intended effect of the compound can become exceptionally challenging. Strategies being explored to promote weight loss include appetite suppression, inhibition of nutrient absorption, and alterations in metabolic function (Appolinario et al, 2004; Clapham, 2004; Jandacek and Woods, 2004; Morris et al, 2004; Small and Bloom, 2004). Regardless of the mechanism of action, many of these compounds will cause weight loss or reduced weight gain in non‐clinical species.…”