Pharma’s Cutting Edge

Obesity-associated improvements in metabolic profile through expansion of adipose tissue

Obesity is bad for you, right?  Not so quick.  It’s been known for decades that deficiencies of fat in unusual to rare syndromes known as lipodystrophies (aka lipoatrophic diabetes) can cause early-onset severe insulin resistance and eventually diabetes.  Based on these cases, clinical researchers surmised that fat isn’t necessarily bad for you–in fact you need some minimum amount of fat to have normal metabolism–and abnormal patterns of fat accumulation, such as an acquired loss of fat in subcutaneous tissues, can trigger insulin resistance and diabetes. 

Since those early clinical studies of lipoatrophic diabetes, many clinical and animal studies have demonstrated that the above is consistently true, and have recently led to a hypothesis that visceral fat (i.e. the fat surrounding internal organs, particularly in the abdomen) is harmful, whereas subcutaneous fat is not and may even help protect against diabetes.  The prevailing theory devised to account for the visceral/subcutaneous fat dichotomy is that triglyceride accumulation within subcutaneous fat serves as a kind of sink that shields vital organs from the sometimes harmful metabolic consequences of intracellular triglycerides (I say sometimes because elite athletes accumulate intracellular fat in muscle tissue without apparent harmful consequences).  In contrast, visceral fat accumulation leads to harmful metabolic consequences because venous drainage of visceral fat feeds fatty acids and glycerol to the liver, where they are reformed in hepatocytes into triglycerides.  Hepatic steatosis results, leading to insulin resistance.  For some unknown reason, says the lipotoxicity theory of diabetes, some people who consume an excess of energy relative to their energy expenditure, are able to accumulate visceral fat more effectively than subcutaneous fat and develop insulin resistance and beta cell failure (as a consequence of fat accumulation in the pancreas), leading to diabetes.  Aside from the “unknown reason” bit, it’s an elegant theory supported by a large body of observational and experimental data in multiple species, including humans.  What has been lacking, however, is an experimental model demonstrating that unconstrained subcutaneous fat expansion allows for development of obesity uncoupled from harmful metabolic consequences (i.e. insulin resistance, beta cell failure and diabetes).

In yesterday’s JCI (link above), Kim et al from Philpp Scherer’s group at UT Southwestern have published detailed descriprions of just such a model.  They created the unusual obesity model by breeding a transgenic mouse that constitutively overexpresses the hormone adiponectin onto an ob/ob mouse background.  The ob/ob mouse is a well described model of congenital leptin deficiency that results in morbid obesity and insulin-resistant diabetes.  Adiponectin is one of the hormones whose expression increases in response to PPAR gamma agonists, like the TZDs pioglitazone (Actos) and rosiglitazone (Avandia), drugs that increase fat mass, primarily subcutaneously, and that also improve insulin resistance.  As it turns out overexpressing adiponectin in leptin-deficient mice leads to diminished food intake (relative to body size) and diminished calorie expenditure (lower activity and lower body temperature) relative to leptin-deficiency alone.  It also leads to fat accumulation and even more weight gain, resulting in massively obese mice.  The balance of energy expenditure and fat accumulation without a change in fat clearance rate suggests enhanced efficiency of fat generation as an important mechanism for obesity in the mice.  Despite the weight gain and fat accumulation, the mice were protected from insulin resistance, beta cell failure and diabetes.  Furthermore, the triglyceride accumulation seen in the organs of leptin-deficient animals was absent in the transgenic animals, as was the associated inflammation (thought to be related to the lipotoxicity of intracellular fat).

Of interest clinically, the transgenic animals, including those bred on a WT background, also developed cardiomyopathy without fat accumulation in heart muscle.  As you’ll recall, as of August, the TZDs now have black-box warnings in their US labels regarding an increased risk of heart failure.  The animal finding suggests that adiponectin might be mechanistically related to the observed heart failure risk.  Keep in mind, though, that Kim et al also found that adiponectin feeds forward to enhance synthesis of PPAR gamma, so it’s not possible to make a TZD-adiponectin link to CHF based on these observations alone.

Although this model probably doesn’t offer any direct uses to drug hunters, it does offer an example of the rescue of a mouse model of obesity-related diabetes through fat accumulation.  In that regard, it serves two important purposes relevant to drug discovery.  First, it adds substantial weight to the lipotoxicity theory of type 2 diabetes, providing a basis for continued drug research in that area.  Many questions remain:  Is it possible to promote subcutaneous lipogenesis without simultaneously promoting morbid obesity?  Can these experimental findings be replicated by manipulating the downstream effectors of adiponectin action in fat; can it be done without promoting cardiomyopathy?  What exactly are the mediators of the toxic effects of triglycerides in liver, muscle and pancreas, and can they be safely interrupted?  Second it provides an animal-model benchmark for drugs intended to disrupt the obesity-diabetes link.  As it happens, the mark for prevention is set pretty high; the mice were completely protected against insulin resistance, beta cell dysfunction, and diabetes resulting from increased food intake.  Of course, the cure also further worsened their already morbid obesity, so there’s still lots of room for improvement. 

In some future post, I’ll discuss what has already been done and what might be done in the future to further test the lipotoxicity/fat deficiency model of diabetes in humans.