WAT-free mice: diabetes without obesity

McKnight, Steven L.

doi:10.1101/gad.12.20.3145

Cited by 7 publications

(7 citation statements)

References 21 publications

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“…lean mice), as in the present study, versus those mice that completely lack adipocytes to store lipid (lipodystrophic mice). Mice that lack adipose tissue completely are uniformly insulin resistant and hyperinsulinemic with markedly increased plasma triglycerides, decreased or absent leptin and accumulation of triglyceride in non adipose tissue sites such as liver and muscle (41,42). In contrast, lean mice (as in the present study) are typically insulin sensitive with normal or increased insulin sensitivity, and normal plasma and liver triglycerides (see review, Ref.…”

Section: %)mentioning

confidence: 56%

Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice

Xia

Stanhope

Digitale

et al. 2004

Journal of Biological Chemistry

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Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(؊/؊) ASP-deficient mice had elevated oxygen consumption (VO 2 ) in both the active (dark) and resting (light) phases of the diurnal cycle: ؉8.9% males (p < 0.05) ؉9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 ؎ 2.4 m whereas KO mice moved 30.1 ؎ 5.4 m, over 12 h, ؉78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p ‫؍‬ 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT ؊68%, WAT ؊29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice. Acylation-stimulating protein (ASP)1 is an adipocyte-derived protein that has potent anabolic effects on human adipose tissue where it increases glucose uptake and non-esterified fatty acid (NEFA) storage (1, 2) via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3, 4) and activation of diacylglycerol acyltransferase (DGAT) (2). These effects appear to be mediated through specific cell surface binding (5, 6) resulting in activation of a signal pathway that includes protein kinase C (7). In addition, ASP has been shown to inhibit hormone-sensitive lipase in adipocytes, independently and additively to insulin (8). There is a differentiation-dependent increase in ASP binding and ASP response in human adipocytes (1). The major site of action of ASP is adipocytes, as determined by competitive binding, stimulation of triglyceride synthesis, enhanced glucose transport, and transporter translocation (5).ASP is identical to C3adesArg, a cleavage product of complement C3. Cleavage of complement C3 is mediated through the alternate complement pathway via the interaction of C3, factor B, and adipsin that generates C3a. Rapid cleavage of the Cterminal arginine of C3a by carboxypeptidase N generates ASP (9). Adipocytes are one of the few cells capable of producing all three factors (factor B, adipsin, and C3) that are required for the production of ASP (10). ASP production increases consequent to a...

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Section: %)mentioning

confidence: 56%

Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice

Xia

Stanhope

Digitale

et al. 2004

Journal of Biological Chemistry

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“…14 However, there is substantial evidence that perturbations of fat cell metabolism can alter insulin-stimulated glucose disposal in vivo to an extent disproportionate to the mass of adipose tissue. 15 This has been taken as an indication of a`long-range' effect of the adipose cell. The mechanism, for this is poorly understood, although a number of factors secreted from adipocytes have been suggested as candidate regulatory molecules.…”

Section: Ceramide Treatment As An In Vitro Model Of Insulin Resistancementioning

confidence: 99%

Insulin signaling in the adipocyte

2000

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“…This is corroborated by recent clinical and animal investigations that excess as well as complete absence of fat in the body are concomitant with hyperinsulinemia, insulin insensitivity and diabetes. 7,[22][23][24][25][26][27][28] The discovery of insulin in 1922 and the subsequent development of insulin analogs have been the life-saving treatments of hyperglycemia and in delaying or preventing the array of chronic complications of diabetes mellitus. 2,13,[29][30][31] Diabetes, therefore, has traditionally been viewed as an affliction of either lack of or incomplete use of insulin and, consequently, conventional research has focused entirely on improving ways to deliver insulin for precision in attaining glycemic control to simulate the physiological range of blood glucose, necessary to combat the comorbidity cluster of this chronic malady.…”

Section: Introductionmentioning

confidence: 99%

“…10,33,51 (3) It is now abundantly clear that diabetes and the antecedent pathophysiologic sequelae-hyperinsulinemia and insulin insensitivity are contemporaneous with either complete leptin deficiency or leptinopenia in rodents and humans. 16,22,23,26,27,52,53 In leptin mutant (ob/ob) mice and congenitally leptin-deficient humans, the incessant hyperphagia and abnormal rate of weight gain are associated with hyperglycemia and hyperinsulinemia. 16,23 Leptin replacement, either systemically or centrally without leakage to the periphery, reinstated euglycemia and normoinsulinemia before any discernible change in appetite or weight.…”

Section: Introductionmentioning

confidence: 99%

“…6,23,[54][55][56] Severe leptinopenia in lean human subjects afflicted with congenital lipoatrophy or in experimentally produced lipodystrophic mice, also conferred hyperglycemia and insulin insensitivity, both readily resolved by leptin replacement therapy. 22,27,52 Similarly, lipoatrophy and leptin deficiency due to wasting inflicted by human immunodeficiency virus infection and treatment of human immunodeficiency virus-infected patients with antiretroviral treatment, are associated with insulin insensitivity and diabetes, both improved by daily leptin replacement. 25,52,[57][58][59] Importantly, these antidiabetic effects of daily leptin replacement manifesting independent of any discernible impact on appetite and weight, involved hypothalamic leptin responsive pathways because mice with conditional leptin receptor knockout in the hypothalamus were diabetic 60 and instillation of leptin receptors selectively in the hypothalamus repressed hyperinsulinemia in the diabetic, leptin receptor mutant rats.…”

Section: Introductionmentioning

confidence: 99%

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Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

Kalra

2011

Gene Ther

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The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

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WAT-free mice: diabetes without obesity

Cited by 7 publications

References 21 publications

Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice

Acylation-stimulating Protein (ASP)/Complement C3adesArg Deficiency Results in Increased Energy Expenditure in Mice

Insulin signaling in the adipocyte

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

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