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Role of A Critical Visceral Adipose Tissue Threshold (CVATT) Part 4

Eric S. Freedland, MD, Boston University School of Medicine. Brings us valuable information on Overnutrition, Lipotoxicity, Leptin, And The Metabolic Syndrome in the next part of The Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome

Role of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome:
Implications for Controlling Dietary Carbohydrates

Eric S. Freedland, MD
Boston University School of Medicine

Part 4
Overnutrition, Lipotoxicity, Leptin, And The Metabolic Syndrome

When one consumes too many calories, especially in the form of excessive carbohydrates, the liver converts excess glucose to fatty acids. First, glucose that is not oxidized or stored as glycogen is metabolized to acetyl CoA, which then enters the lipogenic pathway. Acetyl CoA is catalyzed to form malonyl CoA, which in turn inhibits carnitine palmitoyl transferase 1 (CPT-1, the enzyme responsible for fatty acid transport into the mitochondria) [42]. The net effect is that malonyl CoA (from excess carbohydrates, glucose, and insulin) reduces the oxidation of FAs [150]. This results in increased accumulation of intracellular fat in the form of long chain fatty acids and their derivatives, e.g., TGs and ceramide [29, 30]. Cellular TG accumulation is not initially toxic and may actually be protective by diverting excess FAs from pathways that lead to cytotoxicity [151]. While glucose is being preferentially utilized, the FAs are metabolized by pathways other than their preferred ß oxidation, leading to toxic products, e.g., ceramide, which may cause apoptosis and lipotoxicity [29, 31, 152]. The subsequent development of the cell’s resistance to insulin-mediated glucose uptake, which prevents further influx of glucose, may be viewed as being protective in that it limits the amount of intracellular glucose to be preferentially metabolized over the ß oxidation of intracellular FAs [30, 37, 153]. The cell can be insulin resistant with respect to glucose uptake and metabolism but remain sensitive to insulin’s lipogenic effects and the de novo synthesis of fat. Overconsumption of calories, especially in the form of carbohydrates, also stimulates hyperinsulinemia that can then upregulate SREBP-1c and increase de novo lipogenesis [43].

Leptin protects against lipotoxicity

The first adipocyte-specific hormone to be characterized, leptin is produced predominantly by SCAT adipocytes compared to VAT. Females produce leptin at about twice the rate in males [154], and leptin secretion increases with enlarged adipocyte cell size. Circulating leptin rises by 40 percent after acute overfeeding and more than three-fold after chronic overfeeding, whereas fasting is associated with decreased leptin levels [155].

Dietary carbohydrates may influence leptin action
The increase in leptin concentration after meals is not simply a result of a caloric load, but is in response to a signal that is not present following a fat load without carbohydrate [156]. Leptin circulates in a free form and is also bound to a soluble leptin receptor—sOBR, which is positively associated with energy intake from carbohydrates and negatively associated with energy intake from dietary fat [157].

Excess caloric consumption and fat deposition results in newly synthesized FAs that are transported as VLDLs and stored as TG in adipocytes. Initially, these expanding adipocytes secrete leptin in proportion to their growing fat accumulation. Leptin also crosses the blood brain barrier, stimulates its receptor in the hypothalamus, and causes the release of neuropeptide-Y (NP-Y), which reduces feeding behavior [85]. This, in turn, suppresses appetite and stimulates thyroid function. Leptin affects peripheral tissues, and is a determinant of insulin sensitivity. The ensuing hyperleptinemia increases fat oxidation in skeletal muscle [158-160], and also keeps de novo lipogenesis in check by lowering the involved transcription factor, i.e., SREBP-1c mRNA (sterol regulatory element binding protein 1c mRNA) [43]. It promotes cholesterol ester synthesis in macrophages in a hyperglycemic environment, an important process in the formation of foam cells in atherosclerosis, which may suggest a protective role of relative leptin resistance [161]. Leptin also possibly increases sympathetic nervous system (SNS) activity with subsequent decreased FFA oxidation and thermogenesis [162]. All of these effects of leptin tend to limit further weight gain.

Leptin resistance
As the process progresses, inefficient leptin action can lead to the opposite of leptin’s protective effects, e.g., hyperphagia, decreased fat oxidation, increased tissue TG levels, insulin resistance, and overweight. Subsequently, plasma leptin levels rise. The majority of obese individuals with high leptin levels show a leptin insensitivity or “resistance [163],” which occurs at the leptin receptor level. In animal models, leptin-resistance and leptin-deficiency increases, and upregulates the hepatic expression of SREBP-1c mRNA, which may stimulate an increase in fat production via de novo lipogenesis. Together, all of these features suggest a state of “leptin resistance” which may ultimately lead to obesity and metabolic syndrome [30, 164].

It is quite possible that hyperleptinemia in diet-induced obesity serves to protect nonadipose tissues (e.g. muscles, liver, pancreatic ß cells, and myocardium) from the toxic effects resulting from the spillover of full adipose stores and subsequent ectopic deposition of FFAs. In defense of this paradigm, Unger points out that normally rats can tolerate a 60 percent fat diet because 96 percent of the surplus fat is stored in an enlarging adipose tissue mass, in which leptin gene expression increases proportionally [165]. However, when leptin is congenitally absent or inactive, or ineffective due to resistance, even on a normal or low-fat diet, excess dietary fat is deposited in nonadipose tissues. This causes dysfunction (lipotoxicity), and possible cell death (lipoaptosis) [30].

Acquired leptin resistance occurs in aging, obesity, Cushing’s syndrome, and acquired lipodystrophy, a condition associated with protease inhibitor therapy for AIDS. Preliminary evidence suggests that patients with these conditions have increased ectopic fat, i.e., lipid deposition in non-adipose tissues [30].

Role of triglycerides in leptin resistance
The relation between cerebrospinal fluid and serum levels of leptin in obese humans suggests that defective blood brain barrier (BBB) transport accounts for a great deal of leptin resistance in the CNS. Banks et al showed in mice that serum TGs directly inhibit the transport of leptin across the BBB and so could be a major cause of leptin resistance across the central nervous system (CNS). Thus, they suggest that serum TGs are likely a major cause of the leptin resistance seen in both obesity and starvation [166]. This hypothesis explains why lowering TGs may be therapeutically useful in enhancing the effects of leptin.

Implications for VAT in relative hypoleptinemia and metabolic syndrome
Compared to VAT, SCAT is the predominant source of leptin [60], yet patients with VAT obesity may tend to have higher leptin levels than normal, lean individuals but lower than those with predominantly SCAT or subcutaneous obesity [30]. This suggests that the hyperleptinemia of predominantly VAT obesity is not high enough to overcome a leptin resistance due to the accumulation of ectopic fat in nonadipose tissues, which leads to lipotoxicity and ultimately the metabolic syndrome [30].

Lipodystrophies—A paradigm for the roles of fat depots and insufficient leptin action in metabolic syndrome
A number of clinical states exhibit evidence of leptin insufficiency, either leptin deficiency or resistance, and they all have in common the metabolic syndrome. These include rare genetic diseases known as lipodystrophies, which are characterized by a redistribution of fat. Ironically, in the more severe cases, e.g., congenital generalized lipoatrophy, near-complete fat loss is associated with severe insulin resistance, fatty liver, and classic features of the metabolic syndrome. There is hyperleptinemia along with hyperphagia and a predominance of intra-muscular fat [167]. Dunnigan-type familial partial lipodystrophy is a rare autosomal dominant condition characterized by markedly reduced plasma leptin levels along with gradual loss of SCAT from the extremities, trunk, and gluteal region, commencing at the time of puberty. It also involves hyperinsulinemia, glucose intolerance, dyslipidemia (high TGs with low HDL), and diabetes [168, 169]. These individuals do maintain central obesity and VAT [168], which supports a relatively protective role for SCAT and implicates VAT as being more pathogenic.

The aforementioned potential role of TGs in leptin resistance may have implications for patients with lipodystrophy and lipoatrophy who have little or no fat mass, and as a result, have very little or no leptin. They also have severe hypertriglyceridemia that is reversed by treatment with leptin [167, 170].The elevated plasma level of TGs in these patients is likely inducing leptin resistance that is preventing the leptin from inducing TGs to be used as an energy source. Thus the TGs in these patients are not oxidized, and they are unable to settle into fat stores that would normally act as a TG sink and prevent their diversion to non-adipose tissues where they contribute to lipotoxicity and insulin resistance.

Fat depots can protect against lipotoxicity

Fat provides leptin and adiponectin
Transplantation of adipose tissue grafts in animal models of congenital lipoatrophy reverses the signs of the metabolic syndrome in a dose-dependent fashion [171]. Furthermore, leptin treatment in humans and animals with lipodystrophies also reverses fatty liver and insulin resistance. However, transplantation of ob/ob adipose tissue (which does not produce leptin) in lipodystrophic rats does not reverse diabetes [172] nor is it beneficial to inject leptin in obese humans with leptin resistance [19]. These support the notion that insufficient leptin action may be a cause of metabolic syndrome, and that adequate leptin derived from SCAT is protective.

Like leptin, adiponectin secretion increases early on in obesity.It plays a role in reducing the expression of lipogenic enzymes and increases FA oxidation in peripheral tissues thus limiting ectopic fat accumulation [173]. The fact that adiponectin is secreted initially by fat but levels are reduced as fat depots increase, may help resolve the paradox of both lipodystrophy and obesity both being insulin-resistant states [73].

Next time we get into Critical Visceral Adipose Tissue Threshold (CVATT)—Individual Variations among MONW, MNO patients

Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-2004). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.

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