The prevalence of obesity has risen substantially throughout the world in recent decades. Nonsurgical treatments for reducing adiposity remain paramount to diminishing obesity and its associated comorbidities. Conjugated linoleic acid has received considerable attention due to its ability to reduce body weight and adiposity in a number of species. The mechanisms responsible for adipose depletion by conjugated linoleic acid remain controversial and are not completely understood. The first objective of this research was to determine if conjugated linoleic acid altered adipose phenotype by inducing adaptive thermogenesis and increasing oxidative capacity. In this study, conjugated linoleic acid dramatically reduced weight gain and adipose mass. Additionally, conjugated linoleic acid induced the expression of numerous genes involved in adaptive thermogenesis in epididymal white adipose tissue. Lipid droplet morphology was unchanged by conjugated linoleic acid treatment, although mitochondrial density was increased in epididymal white adipose tissue. Unexpectedly, whole body oxygen consumption and body temperatures were reduced and unchanged by conjugated linoleic acid treatment, respectively. We attributed these observations to a significant reduction in brown adipose tissue with a concomitant compensatory response in epididymal white adipose tissue. Our data suggest that significant reductions in brown adipose tissue by conjugated linoleic acid initiates white adipose adaptive thermogenesis as a means to maintain body temperature.
Although conjugated linoleic acid reduces body weight and adipose mass, it also paradoxically induces lipodystrophy-associated disorders including hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance. The second objective of this research was to determine if hepatic steatosis induced by conjugated linoleic acid would predict for hepatic diacylglycerol accumulation and increased membrane-associated protein kinase C epsilon protein. This study revealed that in addition to increased hepatic triacylglycerol, conjugated linoleic acid increased hepatic diacylglycerol concentration and membrane-associated protein kinase C epsilon. Diacylglycerol concentration positively predicted for fasting hyperglycemia and hyperinsulinemia. The increase in diacylglycerol concentration was also associated with increased hepatic gluconeogenic gene expression in conjugated linoleic acid-treated animals. This study suggested that conjugated linoleic acid initiates the pathophysiology responsible for hepatic insulin resistance. The objective of the third study was to determine if hepatic diacylglycerol accumulation and increased membrane-associated protein kinase C epsilon by conjugated linoleic acid would initiate hepatic insulin resistance. In this study, conjugated linoleic acid induced hyperglycemia and hyperinsulinemia while increasing hepatic lipid deposition. Hepatic diacylglycerol and membrane-associated protein kinase C epsilon were also significantly increased by conjugated linoleic acid treatment. Hyperinsulinemic-euglycemic clamp studies revealed that conjugated linoleic acid caused hepatic insulin resistance, as evidenced by increased endogenous glucose production. Unexpectedly, white adipose tissue glucose disposal was increased by conjugated linoleic acid treatment, whereas skeletal muscle glucose disposal was unchanged. Collectively, these studies demonstrate that conjugated linoleic acid increases epididymal white adipose tissue oxidative capacity, although this alteration is not sufficient to abrogate lipodystrophy-associated disorders that consequently lead to hepatic insulin resistance.