Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice

Kojima, Shinya; Asakawa, Akihiro; Amitani, Haruka; Sakoguchi, Takeo; Ueno, Naohiko; Inui, Akio; Kalra, Satya P.

doi:10.1016/j.peptides.2009.01.007

Cited by 46 publications

(48 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings significantly differ from those of previously published work, in which enhanced CNS LEPR signaling was shown to improve glucose homeostasis in hypoinsulinemic rodents (29). In fact, mainly because (i) leptin and insulin partly share their intracellular signaling pathways (e.g., the PI3K signaling cascade) (21,22) and (ii) leptin has been shown to enhance insulin sensitivity in rodents and humans (19,20,23,24), the effects of central leptin delivery on glucose balance in the context of hypoinsulinemia were likely attributable to synergistic actions between administered leptin and residual insulin.…”

Section: Discussioncontrasting

confidence: 99%

“…Because of the established importance of the CNS in mediating the glycemia-lowering actions of leptin in the context of either a high (17)(18)(19)(20) or low (27)(28)(29) circulating insulin level, we hypothesized that leptin's antidiabetic effects could also be mediated by brain neurons in the context of T1D. To test this hypothesis directly, we assessed the metabolic outcomes of CNSrestricted leptin administration in a mouse model of T1D.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

183

222

View full text Add to dashboard Cite

Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

show abstract

Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

183

222

View full text Add to dashboard Cite

show abstract

“…87,88,98 This regulatory restraint was asserted solely through central pathways because icv rAAV-lep injection in leptin mutant hyperinsulinemic ob/ob mice, consuming either normal chow or energy-enriched diet, normalized blood insulin levels, improved insulin sensitivity along with suppressed adiposity and food intake for the lifetime despite the complete absence of leptin in blood. 54,88 Further, central leptin gene therapy, in a manner quite similar to that observed in insulin-deficient type 1 diabetic rodents, 56,90,96 impelled euglycemia in both normoglycemic and hyperglycemic rodents along with suppressed blood insulin concentrations and improved insulin sensitivity (Figure 1IIb). The novel insight that stable optimal leptin supply can sustain the restraint on insulin hypersecretion in concert with euglycemia for the lifetime of rodents, suggests that central leptin gene therapy has the potential to either delay or permanently block the environmentally acquired type 2 diabetes in the general population.…”

Section: Diabetes Typementioning

confidence: 87%

“…93 The efficacy of circulating leptin was also shown in these paradigms when intravenous infusion of leptin itself for 12 days rapidly impelled normoglycemia with a time course quite similar to that evoked by insulin replacement 94,95 Furthermore, the possibility that restoration of optimal hypothalamic leptin signaling alone imposed euglycemia in these paradigms was verified when leptin supply was endogenously generated solely in the hypothalamus of hyperglycemic streptozotocin-treated mice. 96 An icv rAAV-lep injection 1 week after intravenous streptozotocin administration rapidly suppressed hyperglycemia to within the euglycemic range, and, thereafter, prevented weight loss and early mortality without any discernible behavioral abnormality or diabetic complication through 1 year of observation. 96 Collectively, these findings concur with the new insight that the primary cause of chronic hyperglycemia in diabetics type 1 is the development of leptin insufficiency in the hypothalamus as a consequence of diminished amount of leptin available for entry across the BBB, which can be ameliorated by restoration of optimal leptin supply with gene therapy selectively in the hypothalamus (Figure 1Ib).…”

Section: Diabetes Typementioning

confidence: 99%

“…96 An icv rAAV-lep injection 1 week after intravenous streptozotocin administration rapidly suppressed hyperglycemia to within the euglycemic range, and, thereafter, prevented weight loss and early mortality without any discernible behavioral abnormality or diabetic complication through 1 year of observation. 96 Collectively, these findings concur with the new insight that the primary cause of chronic hyperglycemia in diabetics type 1 is the development of leptin insufficiency in the hypothalamus as a consequence of diminished amount of leptin available for entry across the BBB, which can be ameliorated by restoration of optimal leptin supply with gene therapy selectively in the hypothalamus (Figure 1Ib). …”

Section: Diabetes Typementioning

confidence: 99%

See 1 more Smart Citation

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

Kalra

2011

Gene Ther

View full text Add to dashboard Cite

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.

show abstract

The effect of leptin on maturing porcine oocytes is dependent on glucose concentration

Silva

Paczkowski

Krisher

2012

Molecular Reproduction Devel

View full text Add to dashboard Cite

Increased body weight is often accompanied by increased circulating levels of leptin and glucose, which alters glucose metabolism in various tissues, including perhaps the oocyte. Alteration of glucose metabolism impacts oocyte function and may contribute to the subfertility often associated with obese individuals. The objective of this study was to determine the effect of leptin (0, 10, and 100 ng/ml) on the oocyte and cumulus cells during in vitro maturation under differing glucose concentrations. We examined the effects of leptin on oocyte maturation, blastocyst development, and/or gene expression in oocytes and cumulus cells (IRS1, IGF1, PPARγ, IL6, GLUT1) in a physiological glucose (2 mM) and high glucose (50 mM) environment. We also evaluated the effect of leptin on glucose metabolism via glycolysis and the pentose phosphate pathway. In a physiological glucose environment, leptin did not have an influence on oocyte maturation, blastocyst development, or oocyte gene expression. Expression of GLUT1 in cumulus cells was downregulated with 100 ng/ml leptin treatment, but did not affect oocyte glucose metabolism. In a high glucose environment, oocyte maturation and glycolysis were decreased, but in the presence of 100 ng/ml leptin, these parameters were improved to levels similar to control. This effect is potentially mediated by an upregulation of oocyte IRS1 and a correction of cumulus cell IGF1 expression. The present study demonstrates that in a physiological glucose concentration, leptin plays a negligible role in oocyte function. However, leptin appears to modulate the deleterious impact of a high glucose environment on oocyte function.

show abstract

Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice

Cited by 46 publications

References 32 publications

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

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

The effect of leptin on maturing porcine oocytes is dependent on glucose concentration

Contact Info

Product

Resources

About