Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients?

Figures & data

Figure 1. Six faces of adiposopathy.

Adiposopathy is defined as a pathological adipose tissue dysfunction that may be promoted and exacerbated by fat accumulation (adiposity) and sedentary lifestyle in genetically susceptible patients. In other words, while it is true that modifiable lifestyle choices clearly play a role in fat function and dysfunction, it is also true that the predisposition to dysfunctional fat often has a strong 'chance' genetic component which is not modifiable.

EFRMD: Excessive fat-related metabolic disease; FFA: Free fatty acids

Figure 2. Fat weight gain and metabolically ‘sick’ and ‘healthy’ pathways of storing energy.

Positive caloric balance leads to increased energy storage, which is first achieved through mild adipocyte hypertrophy. Afterwards, continued positive caloric balance may result in a predominance of further adipocyte hypertrophy in which adipose tissue may become dysfunctional or alternatively, a predominance of recruitment of new, functional adipocytes in which overall adipose tissue maintains normal metabolism. The accumulation of visceral fat (and other similar acting fat depots), even by recruitment, proliferation and differentiation, may result in pathological fat dysfunction manifested by an increased net release of free fatty acids and an increased proinflammatory response, which is further amplified by visceral fat hypertrophy.

Table 1. Select comparisons of subcutaneous, peripheral fat versus visceral fat functions* [18,19,223–230].

Characteristics	Function
General characteristics
Fat amount relative to total body fat	Subcutaneous > visceral
Metabolic activity	Subcutaneous < visceral
Greater differentiation of preadipocytes	Subcutaneous > visceral
Apoptosis	Subcutaneous < visceral
Lipolysis/lipogenesis
Inhibition of intra-adipocyte lipolysis by insulin	Subcutaneous > visceral
Inhibition of intra-adipocyte lipolysis by prostaglandins	Subcutaneous > visceral
Inhibition of intra-adipocyte lipolysis by adenosine	Subcutaneous > visceral
Storage of circulating postprandial FFAs	Subcutaneous > visceral
Stimulation of intra-adipocyte lipolysis by catecholamines	Subcutaneous < visceral
Direct access to the liver by portal vein	Subcutaneous < visceral
Increased net adipocyte release of FFAs	Subcutaneous < visceral
Increased portal vein FFAs (and glycerol) increasing hepatic triglyceride and glucose production, thus promoting hyperglycemia and dyslipidemia	Subcutaneous < visceral
Adipocyte receptor activity
Lipolytic β-adrenergic receptors	Subcutaneous < visceral
Antilipolytic-α 2-adrenergic receptors	Subcutaneous > visceral
Glucocorticoid receptors	Subcutaneous < visceral
Androgen receptors	Subcutaneous < visceral
Estrogen receptors	Subcutaneous = visceral^‡
Peroxisome proliferators-activated receptor-γ	Subcutaneous < visceral
Production of adipocyte factors^§
Leptin	Subcutaneous > visceral
Adiponectin	Subcutaneous < visceral
Interleukin-6	Subcutaneous < visceral
Plasminogen activator inhibitor-1	Subcutaneous < visceral
Angiotensinogen	Subcutaneous < visceral
Cholesteryl ester transfer protein	Subcutaneous > visceral
Acylation stimulating protein	Subcutaneous < visceral
Tumor necrosis-α	Subcutaneous < visceral
hormone-sensitive lipase	Subcutaneous > visceral
Lipoprotein lipase	Subcutaneous < visceral
Production of adipocyte factors^§ (cont.).
Retinol binding protein	Subcutaneous = visceral
Insulin-like growth factor-1	Subcutaneous = visceral
Insulin-like growth factor-1 binding protein	Subcutaneous = visceral
Monobutyrin	Subcutaneous = visceral
Uncoupling proteins-1	Subcutaneous > visceral
Uncoupling proteins-2	Subcutaneous > visceral

*Other fat depots (such as abdominal subcutaneous, intraorgan and periorgan fat) may have metabolic activity between that of peripheral subcutaneous fat and visceral fat, have function similar to that of peripheral subcutaneous fat or visceral fat, or have fat function not yet well-defined.

^‡While adipose tissue may contain estrogen receptors, the increase in the subcutaneous, peripheral adipose tissue distribution often found in many women may be more related to estrogen-induced up-regulation of the antilipolytic a 2A-adrenergic receptors found in peripheral subcutaneous fat, and not visceral fat [226].

^§Specific adipocyte factors reflect either increased production or increased gene expression, and the relationships to fat depots are not always consistent in the medical literature. The production and gene expression of adipocyte factors may be influenced by increased fat accumulation.

FFA: Free fatty acid.

Table 2. Adiposopathy interventions and their effects upon select adipocyte factors that may contribute to diabetes mellitus [3].

Adipocyte factors	Hypocaloric diet* and physical exercise*	PPAR-γ agonists	Orlistat	Sibutramine	Cannabinoid receptor antagonists
11- β-hydroxysteroid dehydrogenase type 1	¦	- [79]	?	?	?
Acylation-stimulating protein	Ø	- [231,232]	?	?	?
Adiponectin	¦	↑ [233,234]	↑ [214]	↑/- [235,236]	↑ [237]
Adipsin	-	↑ [238]	?	?	?
Angiotensinogen	Ø	- [231]	?	?	?
Autotaxin	?	↓ [121]	?	?	?
Ceramide	?	↓ [239]	?	?	?
Free fatty acids	Ø	↓ [58,59]	↓ [35,60]	↓/- [61,62]	↓ [63]
hormone-sensitive lipase	↑ / ↓^‡	- [231]	? §	?	?
Interleukin-6	Ø	- [240]	↓ [60,241]	?	?
Insulin-like growth factor activity	¦	↑ [242]	- [243]	?	?
Leptin	Ø	- ↓ [240,231]	↓ [214]	↓ [244]	↓ [245]
Lipin	?	?	?	?	?
Lysophospholipid	?	?	?	?	?
Perilipin	-	↑ [246]	?	?	?
Phospho-enolpyrovate carboxykinase	?	↑ [247]	?	?	?
Plasminogen activator inhibitor-1	Ø	↓/- [231,233,240]	↓ [248]	?	?
Resistin	-	↓ [249]	↓ [97]	↓ [235]	?
Retinol binding protein	?	↓ [195]	?	?	?
Tumor necrosis factor-α	Ø	↓ [240]	↓ [60]	?	↓ [250]
Visceral adipose tissue-derived serpin	?	↑ [208]	?	?	?
Visfatin	Ø	- ↑ [251,252]	?	?	?

*Some adipocyte factors respond differently to acute versus chronic hypocaloric diets and physical exercise. When such conflicts are present, the arrows in this chart represent chronic interventions.

^‡The presence of both an up arrow and a down arrow may represent differing effects of hypocaloric diets versus physical exercise. Please see text discussion.

^§Orlistat is a lipase inhibitor, but its effect is thought to be almost entirely due to impairment of intestinal lipase, as opposed to systemic lipase impairment. In fact, because free fatty acid blood measurements can be difficult, (heparin causes released lipoprotein lipase), the addition of tetrahydrolipstatin or orlistat is a technique used to reduce enzymatic lipolysis and improve the accuracy of free fatty acid levels in blood samples [253].

PPAR: Peroxisome proliferator-activated receptor.

Table 3. Adiposopathy interventions and their effects upon select adipocyte factors that may contribute to hypertension [3].

Adipocyte factors	Weight loss through diet and exercise	PPAR-γ agonists	Orlistat	Sibutramine	Cannabinoid receptor antagonists
11 β-hydroxysteroid dehydrogenase type 1	¦	- [79]	?	?	?
Adiponectin	¦	↑ [233,234]	↑ [214]	↑/- [235,236]	↑ [237]
Free fatty acids	Ø	↓ [58,59]	↓ [60,35]	↓/- [61,62]	↓ [63]
Interleukin-6	Ø	- [240]	↓ [60,241]	?	?
Leptin	Ø	- ↓ [240,231]	↓ [214]	↓ [244]	↓ [245]
Renin-angiotensin-aldosterone enzymes	Ø	- [231,254]	?	?	?

PPAR: Peroxisome proliferator-activated receptor.

Table 4. Adiposopathy interventions and their effects upon select adipocyte factors that may contribute to dyslipidemia [3].

Adipocyte factors	Weight loss through diet and exercise	PPAR-γ agonists	Orlistat	Sibutramine	Cannabinoid receptor antagonists
11 β-hydroxysteroid dehydrogenase type 1 (11HSD1)	¦	- [79]	?	?	?
Acylation-stimulating protein	Ø	- [231,232]	?	?	?
Adiponectin	¦	↑ [233,234]	↑ [214]	↑/- [235,236]	↑ [237]
Adipsin	-	↑ [238]	?	?	?
Cholesterol ester transfer protein (CETP)	Ø	?	?	?	?
Free fatty acids	Ø	↓ [58,59]	↓ [60,35]	↓/- [61,62]	↓ [63]
hormone-sensitive lipase	↑ / ↓^‡	- [231]	? §	?	?
Leptin	Ø	- [240]	↓ [214]	↓ [244]	↓ [245]
Lipoprotein lipase	¦	- [231]	? §	?	↓ [255]
Perilipin	-	↑ [246]	?	?	?
Phospholipid transfer protein	-/↓	?	?	?	?
Androgen	↓ (women) ↑ (men)	↓ / - [256,257]	↓ (women) [258]	↓ (women) [259]	?
Estrogen	-/↓ (men)	↓/- [260,261]	?	?	?

*Some adipocyte factors respond differently to acute versus chronic hypocaloric diets and physical exercise. When such conflicts are present, the arrows in this chart represent chronic interventions.

^‡The presence of both an up arrow and a down arrow may represent differing effects of hypocaloric diets versus physical exercise. Please see text discussion.

^§Orlistat is a lipase inhibitor, but its effect is thought almost entirely due to impairment of intestinal lipase, as opposed to systemic lipase impairment. In fact, because free fatty acid blood measurements can be difficult, (heparin causes release of lipoprotein lipase), the addition of tetrahydrolipstatin or orlistat is a technique used to reduce enzymatic lipolysis and improve the accuracy of free fatty acid levels in blood samples [255].

PPAR: Peroxisome proliferator-activated receptor.

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