Dr. Sharma's Obesity Notes

While some readers may be hoping for the latest diet breakthrough, researchers have now discovered an even easier way to get those calories straight from your lips to your hips.

Thus, according to a paper from Phil Scherer’s lab published in Nature Medicine, the secret ingredient is an unassuming protein that lives in your mitochondria (those crinkly looking cellular powerhouses that run your energy metabolism).

As the story goes, this protein, with the rather memorable name MitoNEET, allows your fat cells to gobble up even more fat, thereby keeping it from ruining the neighbourhood in other organs (like your liver or skeletal muscle).

Evidently, MitoNEET messes up mitochondrial iron transport thereby reducing fat-burn (ß-oxidation), which also leaves you with fewer pro-inflammatory oxygen radicals and more metabolically friendly adiponectin floating around.

So, while an extra dose of MitoNEET may well make you fatter, you can rejoice in the knowledge that this fat is safely tucked away where it belongs, namely in your white fat – point being, it no longer messes with your glucose levels or clogs up your arteries – or at least this is how the story goes if you happen to be a lab mouse.

And woe to those, who lack this fat-enriching protein – they become skinny and unhealthy beings on a down-hill path to certain diabetes, heart disease, and male-pattern baldness (I made up that last one, but it’s probably true).

While anti-obesity activists may wonder about the usefulness of this research, I can certainly see a hot emerging market for MitoNEET analogues in places where beauty is measured in (extra) pounds (like Barbados).

And, if you happen to be one of those healthy obese (EOSS Stage 0) folk, it’s perhaps high time you added MitoNEET to your list of blessings.

AMS
Edmonton, Alberta

Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, Askew GR, Simcox JA, McClain DA, Li C, & Scherer PE (2012). MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nature medicine, 18 (10), 1539-49 PMID: 22961109

Back in 2006 there was a tremendous interest in the biology of peroxisome proliferator-activated receptor gamma (PPARg).

Not only had this nuclear hormone receptor been well recognised as a key regulator of adipocyte differentiation, but the introduction of thiazolidinediones (“glitazones”) in diabetes treatment sparked a tremendous amount of work in this ligand.

In a paper I co-athored with my French colleague Bart Staels, published in the Journal of Clinical Endocrinology and Metabolism in 2006, we reviewed the literature on the role of PPARg in regulating lipid and glucose metabolism in adipose tissue.

Our review included all articles we could find on the role of PPARg in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes published between 1990 and 2006.

As we discuss in detail in the article, PPARg is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage.

In addition, PPARg activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFalpha, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply.

This effects of PPARg-agonists also extends to macrophages, where they suppress production of inflammatory mediators.

Thus, we speculated that PPARg-activating ligands may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

Since then the optimism about this class of medications has been tempered by the fact that larger clinical trials have raised concerns particularly about cardiovascular complications in patients with heart failure.

At the time, however, this state-of-the-art review received considerable attention with over 230 citations to date.

AMS
Edmonton, Alberta

With good access to both adipose tissue biopsies and primary cultured human adipocytes, in the early 2000s, my lab in Berlin continued to conduct a number of exploratory studies on protein expression in human fat tissue.

In 2006, we published a paper in Diabetes, in which we reported the expression of retinol-binding protein 4 in human adipose tissue and showed that it behaved differently than in rodents.

Previous studies in mice had suggested that adipocytes serve as glucose sensors and regulate systemic glucose metabolism through release of serum retinol-binding protein 4 (RBP4).

We did find that RBP4 was highly expressed in isolated mature human adipocytes and secreted by differentiating human adipocytes, however, in contrast to the animal data, RBP4 mRNA was downregulated in subcutaneous adipose tissue of obese women, and circulating RBP4 concentrations were similar in 74 normal weight, overweight, and obese women.

We also found that RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable.

Five percent weight loss slightly decreased adipose RBP4 expression but did not influence circulating RBP4.

In another set of experiments, we stratified 14 volunteers by low or high basal fasting interstitial glucose concentrations, as determined by in-vivo microdialysis technique. Venous glucose concentrations were similar throughout oral glucose tolerance testing, and basal RBP4 expression in adipose tissue and serum RBP4 concentrations were similar in the groups with higher and lower interstitial glucose levels.

Thus, our findings revealed profound differences between what was previously reported in rodents and what we found in humans in the regulation of adipose or circulating RBP4 – in contrast to rodents, it appears that glucose uptake by human adipocytes is not an important determinant in the regulation of RBP4.

Since then, extensive work on the role of RBP4 in glucose homeostasis has continued, which probably explains why this paper has been cited over 240 times.

Edmonton, AB

One of the hypotheses that I developed in the early 2000′s, based on the finding that adipose tissue produces a number of molecules that can directly affect vascular function, was that perivascular fat (found around virtually all blood vessels down to the tiniest arterioles) may play an important role in mediating tissue blood flow.

In a collaboration with Dr. RM Lee at McMaster, in 2006, we published a paper in Cardiovascular Research, in which we reported our finding that perivascular adipose tissue may promote vasoconstriction through the production on superoxide anion.

Using rings of superior mesenteric artery (MA) we fount that rings with intact perivascular adipose tissue (PVAT (+)) showed a greater contractile response to electrical field stimulation (EFS) than rings with PVAT removed (PVAT (-)).

Furthermore, superoxide dismutase (SOD) reduced the contractile response to EFS more in PVAT (+) MA than in PVAT (-) MA.

Inhibitors of NAD(P)H oxidase and cyclooxygenase exerted a greater inhibition on EFS-induced contraction in PVAT (+) MA than in PVAT (-) MA.

We also found that inhibitors of tyrosine kinase (tyrphostin A25) and MAPK/ERK (U 0126) attenuated EFS-induced contraction in PVAT (+) MA in a concentration-related manner, while inactive forms of these inhibitors (tyrphostin A1 and U 0124) did not inhibit the response.

Exogenous superoxide augmented the contractile response to EFS and to phenylephrine in PVAT (-) MA, and this augmentation was blunted by inhibition of tyrosine kinase and MAPK/ERK.

Finally, EFS increased superoxide generation in isolated PVAT and PVAT (+)/(-) MA, which was attenuated by NAD(P)H oxidase inhibition.

We also used RT-PCR to demonstrate the mRNA expression of p(67phox) subunit of NAD(P)H oxidase and immunohistochemical staining confirmed its localization in the adipocytes of PVAT.

Thus, we were able to show that PVAT enhances the arterial contractile response to perivascular nerve stimulation through the production of superoxide mediated by NAD(P)H oxidase, and that this enhancement involves activation of tyrosine kinase and MAPK/ERK pathway.

Since then, many other laboratories have explored the role of perivascular fat in the regulation of vascular function and this has become quite an area of interest for many labs around the world.

According to Google Scholar, this paper has been cited 69 times.

AMS
Gioâna, Brazil

In 2006, we published a paper in Homone and Metabolic Research, in which we reported on endothelial-cell specific molecule-1 (ESM-1), a molecule which inhibits leukocyte adhesion and migration through the endothelium and also happens to be secreted by fat cells.

In this study we looked at ESM-1 expression and regulation in subcutaneous abdominal adipose tissue samples from 70 postmenopausal women.

In cell culture studies we found that mature adipocytes produced more ESM-1 than preadipocytes. We also found that insulin and cortisol inhibited adipocyte ESM-1 production. This inhibitory effect of insulin was attenuated by insulin resistance, as ESM-1 gene expression in subcutaneous adipose tissue was increased in obese, hyperinsulinemic women.

On the other hand, modest 5% weight loss in 14 women did not markedly change gene expression. Circulating ESM-1 levels increased significantly, albeit modestly.

Thus, we confirmed that ESM-1 is actively produced by adipocytes but that circulating ESM-1 levels are reduced in the overweight and obese, consistent with the notion that ESM-1 may play some role in obesity-associated vascular disease.

This clearly did not turn out to be a hotbed of adipocyte research – according to Google Scholar, this paper has only been cited 13 times.

AMS
Orlando, FL