Dr. Sharma's Obesity Notes

Yesterday, I had the pleasure of attending a lecture by Rudy Leibel from Columbia University, who is perhaps best known for his considerable contributions to our current understanding of energy metabolism.

The talk was hosted by William Colmers as part of the University of Alberta Merck Translational Lecture Series.

In his presentation, Leibel addressed the issue of why it is so hard to keep weight off - in fact, even in people who undergo bariatric surgery, weight always comes back when surgery is reversed.

One of the key underlying problems is that when people lose weight, their energy expenditure does not simply fall to that of the energy expenditure of a person ‘naturally’ at that lower weight - it drops to levels far greater than expected.

Thus, a formerly-obese person burns 20% less calories than a never-obese person of that lower weight - or in other words a 200 lb person, who loses 40 lbs burns about 20% fewer calories than someone who is 160 lbs, but has never been obese. On top of this, the formerly-obese person experiences hunger, cold intolerance, and other behavioural and metabolic changes that make sustaining this lower body weight difficult.

From an evolutionary sense, this makes a lot of sense, as maintaining or ‘defending’ fat stores in the past has always been vital for human survival and therefore complex biological systems have evolved to readily take up and store excess calories when available and reduce caloric expenditure when times are tough.

In a large series of carefully conducted energy balance studies in humans, Leibel examined the impact of weight loss on energy expenditure, energy intake, neuroendocrine function, autonomic physiology, metabolism and brain imaging.

Whereas a short-term increase in body weight by 10 % results in a transient increase in energy expenditure, this returns to baseline, when the weight is lost. This means that weight-loss per se does not reduce energy expenditure.

On the other hand, a 10% drop in body weight immediately reduces energy expenditure by as much as 20%.

Interestingly, this fall in energy expenditure is not simply due to a fall in metabolic rate, but largely due to a decline in activity expenditure. This means that the body ’saves’ energy not simply by turning down the furnace, but by becoming substantially more ‘fuel efficient’ during activity. In other words, someone who loses weight, will burn substantially fewer calories for a given amount of exercise than for the same amount of exercise performed before weight loss.

Much of this increase in ‘muscle efficiency’ can be attributed to the remarkable fall in the fat tissue-derived hormone leptin that occurs with weight loss.

Obese individuals apparently need a higher level of leptin to sustain energy balance. When they lose weight, thereby lowering their leptin levels, the system will aim to increase body fat levels to once again produce enough leptin to suppress the orexogenic response. Thus, weight reduction looks like ‘leptin deficiency’ to the brain, which it seeks to correct, by promoting weight gain.

The importance of leptin in this ‘defense’ response is clearly evident from both animal and human studies, in which leptin levels were maintained at or restored to pre-weight loss levels despite weight loss, by injecting leptin at levels just high enough to ‘mimic’ baseline levels.

In all of these experiments, using exogenous leptin to restore leptin levels to baseline, abolished the ‘defense’ mechanisms including the decline in total non-resting energy expenditure, thus making it easier to keep the weight off.

This ‘relative leptin-deficiency’ dependent improvement in muscle efficiency with weight loss can be clearly and consistently demostrated at the functional (exercise), imaging (MRI) and biological (biopsy) level.

Apart from reversing the improvements in muscle efficiency, Leibel also showed how the increased activation of hunger and appetite centres in the brain with weight loss can be reversed by leptin replacement. Thus, administration of leptin to individuals post-weight loss, reverses the decreased/delayed satiation and decreased perception of caloric density that would act to restore body weight to baseline.

Increases in the weight set-point occur with chronic weight gain, neuronal loss of aging, puberty and pregnancy. Unfortunately, lowering this threshold is far less likely, requiring such drastic measures as hypothalamic lesions or cachexia.

Thus, from an energy regulatory perspective, weight loss induces a ‘non-physiological’ state that can be restored to a ‘physiological’ state by leptin administration at levels high enough to mimic baseline levels.

So why is leptin not being sold to maintain weight loss? Because there is currently no regulatory pathway to license drugs that prevent weight regain. Regulators like the FDA and the EMEA simply lack a sound understanding of the complex physiology of weight regulation because after all, in weight management, the problem is never how to lose weight - the problem is always how to keep it off.

Unfortunately, based on the current guidelines for obesity drugs, there is no way for a pharma company to even apply to have a drug licensed that does not help reduce body weight (which leptin does not) but merely helps people keep weight off (which leptin does).

This is a shame, because in the end replacing leptin may well be the safest way to restore the ‘physiological’ state of being obese by correcting the ‘unphysiological’ state of having lost weight, which essentially drives weight regain.

AMS
Edmonton, Alberta

Obesity is rapidly overtaking alcohol as one of the major causes of fatty liver disease.

The term non-alcoholic fatty liver disease (NAFLD) is now widely used to describe hepatic steatosis resulting from excess weight in the absence of a history of significant alcohol use or other known liver diseases.

Already NAFLD is one of the most common liver disease worldwide with approximately 30% of the population affected in industrialized, western countries.

But how exactly does excess weight lead to a fatty liver and how damaging is this effect on liver function?

This is the subject of a comprehensive review by Alexander Wree and colleagues from the University of Duisburg-Essen, Germany, published in the latest issue of DIGESTION.

As the authors point out, visceral adipose tissue secretes free fatty acids (FFAs) and hormones (adipokines) that appear to play a major role in the development of NAFLD. Toxic FFAs can activate the intrinsic apoptosis pathway in hepatocytes (via c-Jun N-terminal kinase_mediated Bax activation) in a process known as ‘lipoapoptosis’. Not surprisingly, apoptotic cell death is a prominent feature in the progression of NAFLD to nonalcoholic steatohepatitis (NASH).

In addition, reduced adiponectin levels commonly associated with obesity may establish a proinflammatory milieu, thus increasing vulnerability to lipotoxicity, which promotes progression from simple steatosis to NASH and even advanced hepatic fibrosis.

Interestingly, obesity also appears to be a significant and independent risk factor for hepatocellular carcinoma, the most frequent type of liver cancer.

There is also data to suggest that excess body weight can adversely affect the progression of chronic hepatitis C and B.

Fortunately, NAFLD is a treatable condition, which responds (often dramatically) to weight loss interventions.

Thus, some readers may be aware that many bariatric surgeons now routinely recommend two weeks of weight loss prior to laparoscopic surgery, as this has been shown to dramatically reduce liver size and improve visibility during the surgical procedure.

As for so many other obesity related conditions, preventing and treating obesity will be a key measure in preventing and controlling this epidemic of fatty liver disease.

AMS
Edmonton, Alberta

Wree A, Kahraman A, Gerken G, & Canbay A (2010). Obesity Affects the Liver - The Link between Adipocytes and Hepatocytes. Digestion, 83 (1-2), 124-133 PMID: 21042023

Prof. Matthias Blüher, Leipzig

This week, I am hosting Matthias Blüher, Professor of Endocrinology from the University of Leipzig, Germany, who yesterday, presented a seminar on the topic of “Insulin Sensitive Obesity” at the Alberta Diabetes Institute.

As most readers will know, excess weight is typically associated with insulin resistance, which has been suggested to be a major underlying factor in the development of the metabolic syndrome.

However, as Blüher and other have shown before, there is a significant subset of individuals with excess weight, who are quite insulin sensitive and lack any sign or evidence for metabolic abnormalities. These individuals have also been described as being “metabolically healthy obese”.

Blüher’s group in Leipzig has performed extensive studies on this interesting group of subjects, which make up around 10-25% of individuals with severe obesity.

Using euglycemic insulin clamp studies (the gold-standard for measuring insulin sensitivity), Blüher and colleagues identified 30 individuals with typical insulin resistance and 30 individuals with atypical insulin sensitivity - both groups of subjects had a mean BMI of around 45 or severe obesity.

Among the many differences between the two groups, the best predictor of insulin resistance included more liver fat and increased visceral fat.

As reported previously, insulin resistant individuals had higher levels of glucose, HbA1c (although diabetic patients were excluded from the study), lower levels of HDL choldesterol, higher levels of CRP, larger adipocytes, greater macrophage infiltration of adipose tissue, and a higher leptin-to-adiponectin ratio.

Expression studies on fat tissue from both groups showed higher expression of various adipokines and biomarkers including AGT, MCP-1, PAI-1, Nampt (visfatin) endocannabinoids, ceramide, and oxidative stress in the insulin resistant group than the insulin sensitive controls.

In contrast, adipose tissue of the insulin sensitive subjects expressed higher levels of FTO, UCP-1, and adiponectin.

Blüher and colleagues were particularly thrilled to also see increased expression of vaspin (Visceral adipose tissue – derived serpin A12) in the insulin sensitive group, an enzyme that has been shown to increase insulin sensitivity and reduce food intake in animal studies. This molecule may provide a “drugable” target for treating obesity or related metabolic complications in the future.

Much of this work was undertaken as part of the newly funded Integrated Research and Management Centre for Obesity, which was recently funded by the German federal government in Leipzig.

As we discussed during Blüher’s meeting, we very much look forward to developing and expanding collaborations between the University of Alberta and the University of Leipzig as part of the recently negotiated Alberta-Saxony cooperation agreement.

I certainly look forward to working closely with Blüher and his colleagues over the coming years.

AMS
Edmonton, Alberta

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Klöting N, Fasshauer M, Dietrich A, Kovacs P, Schön MR, Kern M, Stumvoll M, & Blüher M (2010). Insulin-sensitive obesity. American journal of physiology. Endocrinology and metabolism, 299 (3) PMID: 20570822

Yesterday, I co-chaired and spoke at a session on obesity management at the 25th Annual Scientific Meeting of the American Society of Hypertension in New York.

Later in the afternoon, Jeff Friedman, who played a prominent role in the discovery of leptin, thereby hearkening in the modern era of adipocyte and appetite physiology, presented an update on the potential role of this system in the therapeutic management of obesity and diabetes.

While leptin has therapeutic efficacy in rare cases of genetic leptin deficiency, its use in non-genetic “garden-variety” obesity has proven disappointing. Indeed, there appears to be more evidence that leptin plays an important role in defending against weight loss, than to support its roled in the prevention of weight gain.

Thus, the dramatic decline in sympathetic activity, fall in metabolic rate and increased hunger that follows weight loss is likely due to the decrease in the leptin signal that unleashes the biological drive to rapidly regain weight and defend against further weight loss.

Indeed in most obese individuals, leptin levels increase in proportion to weight gain, while at the same time these individuals display leptin resistance, rendering these increased levels of leptin as biologically ineffective (a notion akin to the hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes mellitus).

This state of affairs limits the use of leptin for the treatment of obesity, as the high doses of leptin that would be required to overcome the leptin resistance are poorly tolerated.

But recent research points to another possible use of leptin (or leptin analogues) in weight management, namely as a way to prevent weight regain after weight loss.

The basic idea here is to substitute leptin after weight loss in an attempt to trick the body into thinking that it still has as much body fat as it had before. Studies that have combined the peptide pramlinitide (which induces weight loss) with metreleptin (a long-acting analogue of leptin) are showing promise in terms of long-term weight loss maintenance (albeit at the cost of injections).

Friedman also discussed new data showing that leptin may have potent antidiabetogenic effects independent of any effects on weight loss or food intake. Some of this action may be mediated by leptin’s ability to increase plasma levels of Insulin-like Growth Factor Binding Protein 2 (IGFBP2), which has profound inhibitory effects on hepatic glucose output.

Several studies to further exploring the interaction between leptin and IGFBP2 and the antidiabetic effect of this protein are currently underway in Freidman’s lab to better understand these novel findings.

AMS
New York, New York

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Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, & Friedman JM (2010). Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism, 11 (1), 11-22 PMID: 20074524