Is The Ob Gene Found Only In Animals, Or Do Humans Have It Also?

• Journal List
• Proc Natl Acad Sci U S A
• five.95(20); 1998 Sep 29
• PMC21729

Proc Natl Acad Sci U S A. 1998 Sep 29; 95(20): 11852–11857.

Medical Sciences

Aberrant regulation of the leptin gene in the pathogenesis of obesity

Ella Ioffe

^*Howard Hughes Medical Institute, ^†The Rockefeller University, 1230 York Avenue, New York, NY 10021

Byoung Moon

^*Howard Hughes Medical Constitute, ^†The Rockefeller University, 1230 York Avenue, New York, NY 10021

Eileen Connolly

^*Howard Hughes Medical Establish, ^†The Rockefeller Academy, 1230 York Avenue, New York, NY 10021

Jeffrey M. Friedman

^*Howard Hughes Medical Institute, ^†The Rockefeller Academy, 1230 York Avenue, New York, NY 10021

Received 1998 Jun xix; Accepted 1998 Jul 30.

Abstract

A subset of obese humans has relatively low plasma levels of leptin. This finding has suggested that in some cases abnormal regulation of the leptin factor in adipose tissue is etiologic in the pathogenesis of the obese state. The possibility that a relative decrease in leptin product can lead to obesity was tested by mating animals carrying a weakly expressed adipocyte specific aP2-homo leptin transgene to C57BL/6J ob/ob mice (which practice non express leptin). The transgene does not comprise the regulatory elements of the leptin gene and is analogous to a circumstance in which the cis elements and/or trans factors regulating leptin RNA production are abnormal. The ob/ob mice carrying the transgene had a plasma leptin level of i.78 ng/ml, which is ≈half that constitute in normal, nontransgenic mice (iii.72 ng/ml, P < 0.01). The ob/ob animals expressing the leptin transgene were markedly obese though non as obese as ob/ob mice without the transgene. The infertility as well equally several of the endocrine abnormalities by and large evident in ob/ob mice were normalized in the ob/ob transgenic mice. Yet, the ob/ob transgenic mice had an abnormal response when placed at an ambient temperature of 4°C, suggesting that dissimilar thresholds exist for the different biologic effects of leptin. Leptin treatment of the ob/ob transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wild-type mice. In aggregate these data propose that dysregulation of leptin gene can result in obesity with relatively normal levels of leptin and that this form of obesity is responsive to leptin handling.

Many clinical studies have suggested the hypothesis that torso weight is regulated past a "set signal mechanism" (1–3). This hypothesis holds that individuals reach equilibrium at different weights. Information technology is posited that when individuals are at their set signal, compensatory mechanisms resist weight modify in either direction. The observation that weight loss in both lean and obese subjects is associated with reduced energy expenditure supports the ready indicate hypothesis as does the high recidivism charge per unit among obese subjects who lose weight by dieting (4, 5).

A possible molecular basis for differences in weight among individuals has been suggested with the cloning of the ob cistron and the identification of leptin (6–12). In principle, differences in leptin sensitivity and/or product of leptin could lead to differences in weight. It has been suggested that loftier plasma levels of leptin and/or increased levels of leptin RNA in obese subjects is indicative of leptin resistance (13–17). Indeed, 90–95% of obese humans take loftier leptin levels as practise all forms of rodent obesity that have been analyzed (with the exception of leptin-deficient ob/ob mice). Treatment of several strains of obese rodents with leptin has confirmed that high leptin levels point complete or partial leptin resistance (18, 19).

A subset of obese humans have normal or relatively low leptin levels (≈5–10% of subjects) (13, 14). In these individuals, information technology has been postulated that a decreased rate of leptin production by adipose tissue is causal of the obese land. If truthful, a fractional decrease in the activeness of the leptin gene should result in obesity with normal leptin sensitivity. To test this hypothesis, transgenic mice expressing a weak leptin transgene were bred to ob/ob mice. Constitutive expression of leptin at a low level in the ob/ob transgenic mice resulted in a moderately obese phenotype that is less severe than that seen in standard C57BL/6J ob/ob mice. In addition, the ob/ob transgenic mice manifest some, merely not all, of the abnormalities generally seen in C57BL/6J ob/ob mice (three). These data suggest that different thresholds exist for the different biologic responses elicited by quantitative differences in leptin concentration.

ob/ob mice expressing the transgene are quite obese with 30% body fatty, a level 3-fold higher than that of wild-type mice. Handling of these animals with low doses of leptin results in the loss of copious amounts of weight. These data have implications for the pathogenesis of homo obesity and may indicate that the subset of individuals with low leptin obesity volition respond robustly to leptin handling.

METHODS

Transgene Construction and Production of Transgenic Mice.

A human being leptin transgene was constructed by ligating the 5.4-kb aP2 promoter fragment to a 1-kb fragment of human leptin cDNA, followed by a simian virus xl (SV40) polyadenylation betoken (4, 5). Transgene DNA was injected into FVB/Due north embryos to produce transgenic mice. The transgenic mice were identified by PCR amplification of genomic DNA from their tail tips past using SV40 poly(A)-derived oligonucleotides simian virus F, 5′-TCTTTGTGAAGGAACCTTAC-3′, and Rous sarcoma virus, 5′-GGAATCTAAAATACACAAAC-3′, to produce a diagnostic PCR fragment of 233 bp. A transgenic founder with normal body weight and depression plasma level of human being leptin was bred to the C57BL/6 ob/+ mice and intercrossed. The transgene was backcrossed onto the C57BL/6J background for at least six generations before being studied.

Animal Maintenance and Analysis.

Animals were housed in groups of one–v on a 12-hr light/dark bicycle on a standard chow nutrition and weighed weekly or daily during leptin infusion. All animals were typed by PCR for the presence of human being leptin transgene every bit described in a higher place. The ob genotype was determined by PCR using oligonucleotides 5′-GCCATCCAGGCTCTCTGG-3′ and 5′-TGAGTTTGTCCAAGATGGACC-3′, with subsequent digestion of the PCR product with the DdeI restriction enzyme. Fertility was tested past housing each mouse with a proven breeder of the opposite sexual practice for at least a week. Animals were considered fertile if a litter was subsequently built-in. Sensitivity to cold was tested by placing animals in private cages without food and h2o in a cold room at a temperature of iv°C. Trunk temperatures were measured with a rectal thermometer every 1 60 minutes.

Leptin Infusion and Assay of Body Composition.

Transgenic ob/ob males were separated into individual cages with advertisement libitum access to a standard chow diet and water, and their body weights and food intakes were monitored daily until stabile. Daily diet intake was determined past weighing the food remaining in each cage each 24-hour period. Subcutaneous Alzet 14-day osmotic pumps filled with either PBS or recombinant murine leptin (pumping rate 400 ng/hr) were implanted as described (xviii). All pumps were replaced after 14 days at which fourth dimension fresh pumps were placed for an additional xiv days. Blood was collected by intraocular haemorrhage into tubes containing EDTA and separated into plasma. Body composition analysis was performed as described (7).

Decision of Endocrine Parameters.

Plasma was collected, and 50 μl was assayed past using human being or mouse leptin RIA kits (Linco Research Immunoassay, St. Charles, MO) to determine serum leptin concentrations. Human leptin concentration in plasma also was adamant by ELISA using a polyclonal antibody against recombinant human leptin, which was cross-purified confronting mouse plasma. Plasma insulin was quantitated with a rat insulin RIA kit (Linco), corticosterone concentration was determined by using an RIA kit for rats and mice (ICN), and total T4 was measured with an RIA kit (Diagnostic Products, Los Angeles). Claret glucose was quantitated by using the SureStep Complete Claret Glucose Monitoring System (Johnson and Johnson, Milpitas, CA).

Reverse Transcription–PCR and Northern Blot Analyses.

Total RNA was prepared from mouse tissues by using RNAzol B reagent (Tel-Exam, Friendswood, TX). RNA from white adipose tissue were subjected to reverse transcription–PCR analysis by using the specific primers described above. Northern analysis was performed on 20 μg of total RNA from each tissue. Blots were probed with PCR-labeled man leptin cDNA fragment using primers five′-TGTCACCAGGATCAATGACA-3′ and v′-TGGCAGCTCTTAGAGAAGGCC-3′. Blots were hybridized for 4 60 minutes in Rapid-hyb buffer (Amersham) and exposed to Reflection autoradiography film (NEN) with a screen for 64 hr.

Determination of Adipose Cell Size and Number.

Parametrial, retroperitoneal, and subcutaneous fat pads were dissected from ob/ob and ob/+ transgenic and nontransgenic mice at ix–14 weeks of historic period as described (21). Tissues were washed with warm saline, and 100-mg samples from each tissue were prepared. 2 representative samples from each fatty pad were used to determine adipocyte size past extraction with chloroform-methanol. Two more samples from each fatty pad were used for determination of adipocytes number by using fixation with osmium tetroxide as described (21). The number of fatty cells was estimated past counting 4 aliquots from each sample and averaging the results. The values derived independently from each pair of samples from the same fatty pad were considered accurate if they differed from each other by less then ten%.

RESULTS

A transgenic founder mouse carrying a weakly expressed human leptin transgene was generated by ligating the fat-specific aP2 promoter to a human leptin cDNA with a simian virus 40 poly(A) site (Fig. ​ 1, Lower). The 5.4-kb aP2 promoter leads to expression of transgenes specifically in adipose tissue (22, 23). A transgenic animate being expressing low levels of human leptin was identified. The plasma level of human leptin in this founder creature was 1.5 ng/ml equally determined past using an RIA specific for human leptin. This level is ≈50% lower than the plasma leptin levels in wild-blazon mice (three.72 ng/ml). The transgenic founder was bred to C57BL/6J ob/+ mice. ob/+ animals were identified by digesting a PCR product spanning the C57BL/6J ob/ob missense mutation with DdeI (24). The PCR product from the mutant gene is digested by DdeI, whereas the wild-type one is not (data not shown). The transgene was backcrossed onto the C57BL/6J ob/ob strain for at to the lowest degree 6 generations before any experiments were performed. ob/ob mice conveying the transgene were identified amid the progeny of genetic crosses between ob/+ and ob/ob transgenic mice (ob/ob mice are generally infertile but the ob/ob transgenic mice breed normally, encounter beneath) (three, 25, 26). Deoxyribonucleic acid was prepared from the progeny of this mating and used to assign genotype at the ob locus and to determine which of the mice carried the transgene. Iv groups of mice were characterized: ob/+, ob/+ TG, ob/ob, and ob/ob TG (TG refers to the transgene).

Human being leptin transgene and its expression blueprint. A transgenic mouse expressing a leptin transgene was generated. The construct is shown at the bottom. The founder was bred into the C57BL/6J ob/ob groundwork for vi or more than generations. Four groups were studied: ob/+, ob/+ TG, ob/ob, and ob/ob TG. A Northern blot of total RNA from tissues of ob/+ and ob/ob transgenic and nontransgenic mice was probed with a labeled homo leptin cDNA fragment. A positive signal was detectable simply in white adipose tissue of transgenic mice. The probe did not notice RNA in whatsoever tissues of the nontransgenic mice.

The expression of the transgene was assessed past using Northern blots probed with a fragment of the human leptin gene (Fig. ​ 1). Northern blots indicated that the transgene was expressed only in adipose tissue. Reverse transcription–PCR using primers derived from the simian virus forty sequence at the iii′ end of the transgene RNA yielded similar results (data not shown). The indicate intensity of the transgene on Northern blots was not unlike in the ob/+ TG and the ob/ob TG groups. The size of the transgenic RNA was ≈ii.v kb, which is essentially shorter than the four.5-kb wild-type leptin transcript. Signals were non detected in mice that did not carry the transgene, indicating that the human leptin probe did non crossreact with the endogenous RNA in ob/+ TG mice. Although the RNA bands detected on Northern blots were rather diffuse, the bands detected by using a glyceraldehyde-iii-phosphate dehydrogenase probe were non (data not shown). The basis for the variable size of RNAs expressed from the transgene is not clear merely may indicate that the RNA is unstable. It has been suggested that RNA expressed from transgenes that do not include introns is frequently unstable.

The leptin levels of the 4 groups of mice were measured past using RIAs specific for either mouse or human leptin (Tabular array ​ 1). The plasma level of human leptin was equivalent in ob/+ TG and ob/ob TG mice (1.81 vs. 1.78 ng/ml, see Tabular array ​ i for values in males and females). Mouse leptin was non detected in ob/ob mice not carrying the transgene. The concentration of endogenous mouse leptin was non significantly different in the ob/+ TG mice vs. the ob/+ animals not carrying the transgene (3.17 ng/ml vs. 3.72 ng/ml, see Tabular array ​ i for values in males and females).

Table 1

Phenotypic features of the ob/ob, ob/ob TG, ob/+, and ob/+ TG mice

	Males				Females
	ob/+ TG	ob/+ None	ob/ob TG	ob/ob None	ob/+ TG	ob/+ None	ob/ob TG	ob/ob None
Plasma mouse leptin (ng/ml)	2.80	3.49	0	0	3.60	iv.04	0	0
	(±0.96)	(±1.89)	(±0)	(±0)	(±0.39)	(±2.65)	(±0)	(±0)
Plasma human leptin (ng/ml)	i.54	0	i.68	0	2.19	0	1.xc	0
	(±0.42)	(±0)	(±0.48)	(±0)	(±0.34)	(±0)	(±0.60)	(±0)
Blood glucose (mg/dl)	162.ix	171.viii	144.8	265.2	134.7	147.3	150.9	228.4
	(±23.7)	(±14.two)	(±19.iii)	(±74.ix)	(±10.iv)	(±twenty.1)	(±xiv.three)	(±51)
Plasma insulin (ng/ml)	0.lxx	1.49	2.42	28.62	0.52	0.61	ane.60	7.55
	(±0.36)	(±0.xc)	(±1.08)	(±14.19)	(±0.xi)	(±0.17)	(±0.77)	(±7.27)
Plasma corticosterone (ng/ml)	132.3	94.6	85.7	248.1	107.3	122.nine	152.2	210.three
	(±81.9)	(±41.7)	(±36.7)	(±58.0)	(±48.2)	(±57.eight)	(±41.4)	(±45.8)
Plasma thyroxine (μg/dl)	3.52	3.23	4.00	3.35	3.67	iii.88	four.97	3.54
	(±1.25)	(±0.85)	(±one.00)	(±0.53)	(±1.64)	(±0.58)	(±0.83)	(±0.44)
Fertility (%)	6/half dozen	three/3	half dozen/6	0/5	six/6	ten/ten	10/12	0/v
	(100%)	(100%)	(100%)	(0%)	(100%)	(100%)	(83%)	(0%)
Litter size					five.seven (±2.7)	seven.3 (±2.seven)	5.0 (±ane.iii)	0
n					xi	ix	vi	0

The growth curves of the four groups of animals was compared by measuring torso mass every week (Fig. ​ 2 A). All animals were fed a standard grub diet. At that place was no departure in the growth rates betwixt the ob/+ mice with and without the transgene. There was a marked deviation nonetheless, amongst ob/ob TG mice, the ob/ob mice without the transgene, and wild-blazon mice. At all time points after 4 weeks, the ob/ob TG mice had an increased weight relative to wild-blazon mice but weighed less than the ob/ob mice not carrying the transgene (Fig. ​ 2 A). At half-dozen months the average weight of the ob/ob TG mice was 42.5 g in males and 38.2 g in females. The ob/ob males weighed 65.6 chiliad and females weighed threescore.vii g. The wild-type males weighed 31.v m and the females weighed 25.9 thousand. Analysis of the trunk limerick of the ob/ob TG indicated that they had ≈30% body fat, a ≈iii-fold increase relative to the wild-type mice (see Fig. ​ 3 B). The percentage of fat of the ob/ob TG mice was ii-fold lower than that reported for ob/ob mice (seven).

Phenotype of ob/ob TG mice. (A) The body weight of the ob/ob TG, ob/+ TG, and ob/+ mice was measured every week. At all times by four weeks, ob/ob TG mice were significantly larger that the wild-blazon mice though not as heavy as ob/ob mice. All animals were fed a standard chow nutrition. Data for males and females are shown. (B) The adipocyte cell size was equivalent in the ob/ob TG and ob/ob mice but larger than that of wild-type mice. In contrast, the adipocyte cell number was increased ≈2.v-fold in the ob/ob mice. Thus the ob/ob TG take a hypertrophic form of obesity. (C) The response to an ambient temperature of iv°C was compared among the 4 groups. In contrast to wild-type mice, which maintain a normal core temperature, the ob/ob TG mice became hypothermic after 6 60 minutes at four°C. The ob/ob mice became hypothermic later on 2 hr.

Response of ob/ob TG mice to leptin treatment. Leptin (400 ng/ml) or PBS was delivered to groups of five ob/ob TG mice as a 28-solar day s.c. infusion by using Alzet osmotuic pumps. (A) The nutrient intake and body weights of mice were measured daily. Data are shown every bit mean ± SD. Leptin handling resulted in a marked decrease in food intake and body weight. (B) Leptin treatment of the ob/ob TG mice resulted in a decrease in torso fat content from thirty% to three%. The treatment did non affect lean body mass or the amount of body water.

Obesity tin can exist the issue of hyperplasia and/or hypertrophy of adipocytes (27). The fat cell numbers and fatty jail cell size were compared in several adipose tissue depots of ob/ob TG, ob/ob, and wild-blazon mice (Fig. ​ two B). Equally previously reported, ob/ob mice have both an increased number of fat cells and an increased fatty jail cell size relative to wild blazon (21). In contrast, adipose tissue from the ob/ob TG mice had cells with a size like to the ob/ob mice only independent ≈2.five-fold fewer cells. The ob/ob TG mice had a small increase in the number of fat cells every bit compared with the wild-type mice. These information betoken that the obesity of ob/ob TG mice is primarily a upshot of adipocyte hypertroply.

ob/ob animals manifest a number of abnormalities too obesity, including infertility, severe insulin-resistant diabetes, abnormal thermoregulation, and hypercortisolemia (3, 25). Assays to examination for the presence of these abnormalities were performed (Table ​ i). Although none of x ob/ob animals (five males, 5 females) were successfully bred, half dozen/6 ob/ob TG males and x/12 ob/ob TG females yielded progeny in test matings. ob/ob mice were severely insulin resistant and diabetic with blood glucose in the range of 228–265 ng/dl and a markedly increased level of plasma insulin of 28.62 ng/ml. ob/ob TG mice had normal plasma glucose levels although plasma insulin was 2-fold elevated, indicating the presence of mild insulin resistance. Of interest, the ob/+ transgenic mice had lower plasma insulin compared with the nontransgenic groups, suggesting that they may exist especially insulin sensitive. The hypercortisolemia evident in ob/ob mice also was normalized in the ob/ob mice carrying the transgene (248 ng/ml in ob/ob mice vs. 85.7 ng/ml in ob/ob TG mice).

Abnormalities in thermoregulation in response to a cold stress were axiomatic in the ob/ob TG animals (Fig. ​ 2 C). Wild-type mice maintained a cadre temperature of 32.65 ± 4.42 after vi hour at an ambience temperature of 4°C. Every bit previously reported C57BL/6J ob/ob mice do non tolerate common cold exposure and exhibited a marked decrease in core temperature later 2 hr at 4°C. ob/ob TG mice have an intermediate phenotype and showed a significantly decreased temperature subsequently 4–6 hr at 4°C (32.6°C vs. 23.7°C, P < 0.02).

The efficacy of leptin treatment of the ob/ob TG mice was studied. Leptin (400 ng/hr) or PBS was infused s.c. into groups of ob/ob TG mice by using Alzet osmotic pumps (Fig. ​ 3A). A due south.c. leptin dose of 400 ng/hr is sufficient to markedly reduce body fat content in wild-type mice merely is ineffective in leptin-resistant NZO and A^y mice (18). ob/ob TG mice treated with leptin consumed significantly less food relative to the PBS-treated group (83.4 grand vs. 127.ane g, P < 0.001) and lost copious amounts of weight (Fig. ​ iii A). Weight loss was specific for adipose tissue mass, and the amount of torso fat fell from an boilerplate of 30.55% in the PBS groups vs. 3.36% in the treated grouping (Fig. ​ 3 B). Treatment of the ob/ob TG mice with leptin as well was associated with a decrease in the plasma levels of glucose and insulin (glucose 116.viii ng/ml, insulin 0.29 ng/ml in the treated group; glucose 208.6 ng/ml, insulin ii.44 ng/ml in the PBS-treated group).

DISCUSSION

Differences in leptin sensitivity and/or leptin product have been suggested to play a role in the pathogenesis of obesity. The majority of human and rodent obesity is associated with hyperleptinemia, suggesting that in these cases leptin resistance is responsible for this status (13–17). This conclusion is supported past the observed insensitivity to exogenous leptin in DIO, A^y, and NZO mice (eighteen, xix). However, approximately 5–x% of obese humans take relatively normal leptin levels (i.east., below x ng/ml) (13, xiv). It has been suggested that in these cases, obesity is a effect of a relative decrease in the synthesis of leptin RNA and/or protein. If truthful, abnormal regulation of the leptin factor leading to constitutive expression of a small amount of leptin should result in obesity. Moreover this form of obesity should be remediable with leptin handling.

The hypothesis that aberrant gene regulation can crusade obesity was tested past convenance a weakly expressed leptin transgene. In these studies, the consequence of the transgene, which is the only source of homo leptin, was compared amongst animals with different ob genotypes. The choice of the transgene every bit leptin "delivery tool" rather than administration of exogenous leptin was justified by our interest in the phenotypic consequences of a slightly decreased leptin level in animals that expressed information technology beginning in the neonatal period standing into adulthood. This arroyo allowed u.s. to predict the likely phenotype of an individual with a "regulatory" defect that results in a constitutively decreased charge per unit of leptin production. It would not have been viable to implant an infusion pump continuously from the neonatal period onward, nor could we have reliably estimated the leptin levels that were achieved. In addition, the bioactivity of recombinant leptin may change over a long time and is not necessarily equivalent to that of leptin produced in vivo. Finally, pump insertion leads to a number of responses, stresses the animals, and invariably causes infections if maintained for the several months. Injections of leptin would be fifty-fifty less suitable than infusion pumps. Thus, the employ of mice carrying leptin transgene was essential for the comport of these studies.

ob/ob mice carrying the leptin transgene expressed relatively depression levels of leptin and were markedly obese. In addition, many of the features of the ob phenotype were mitigated past the low level of leptin expressed from the transgene. Unlike ob/ob mice, the ob/ob TG animals are fertile, have relatively normal plasma corticosterone levels, and are nondiabetic (iii, 25). Thus leptin circulating at a level of 1.5 ng/ml is sufficient to foreclose these abnormalities. The ob/ob TG mice exercise showroom mild insulin resistance as evidenced by the presence of balmy hyperinsulinemia in the presence of normal glucose levels. This finding suggests that mild insulin resistance, which generally is associated with obesity, can be seen in the absence of hyperleptinemia.

The ob/ob mice expressing the transgene did non respond unremarkably to cold stress. This abnormality suggests that the threshold for the various responses to leptin are set at different levels (Fig. ​ four). Although the leptin level of 1.5 ng/ml expressed in the ob/ob TG mice is sufficient to right several of the endocrine abnormalities of ob/ob mice, they are non adequate to completely normalize body weight and cold tolerance. Several lines of evidence suggest that the hypothalamus is an important site of leptin action (ix, 10, 18, 28). The mechanisms by which the hypothalamus senses quantitative differences in leptin level are not understood. These data may indicate that neurons expressing the leptin receptor activate different pathways in response to different concentrations of leptin. Alternatively, the leptin receptor positive neurons that command body fat content and thermoregulation may be distinct from those that lead to infertility and hypercortisolemia in the consummate absence of leptin.

Responses to quantitative changes in leptin level. Different biological responses to leptin are observed at different plasma concentrations. The complete absenteeism of leptin leads to a markedly abnormal phenotype. Slightly subnormal levels ameliorate many of the features of leptin-deficient animals just is associated with common cold intolerance and moderate obesity. Finally, physiologic increases in leptin levels decrease body fat. The molecular basis for the different physiologic responses elicited at various leptin concentration is non known.

The ob/ob TG and ob/ob mice carrying the transgene likewise differed with respect to the cellularity of adipose tissue. Significant hyperplasia is non seen in the ob/ob TG mice, suggesting that partial leptin deficiency induces adipocyte hypertrophy. This finding is in contrast to complete leptin deficiency, which also leads to increased adipocyte proliferation and/or differentiation. Thus the low levels of leptin expressed in the ob/ob TG mice are apparently sufficient to blunt the hyperplasia of adipose tissue seen in the complete absenteeism of leptin. The high authorization of leptin administered intracerebroventricularly suggests that leptin'southward effects on adipose tissue are probable to be controlled by efferent signals coming from the central nervous organization (9, 18). Although the nature of this signal(southward) is unclear, it has been suggested that leptin increases the activity of the sympathetic nervous system, which may mediate some of its furnishings on adipose tissue (29). The in vivo signaling mechanisms that regulate adipose jail cell proliferation and/or differentiation are largely unknown only may include PPARγ2 and its ligand as well as the recently cloned dark-brown adipose tissue coactivator poly peptide, PGC-i (30, 31).

It has been previously reported that mutations in the leptin gene result in obesity in humans and rodents (half-dozen, 20, 32). The data presented here indicate that abnormal regulation of the leptin factor resulting in a quantitative decrease in leptin product also tin can cause obesity. These results have important implications for the subset of obese individuals who have relatively normal plasma levels of leptin and suggests that these individuals may accept a relative decrease in the rate of leptin production. The molecular mechanisms that regulate leptin synthesis in relation to the corporeality of adipose tissue are not known. These data suggest the possibility that variation in the genes controlling the charge per unit of leptin production tin lead to differences in body weight. Further studies to identify the factors regulating leptin synthesis and secretion may be of import for the elucidation of the pathogenesis of obesity in euleptinemic obese subjects. The robust response of the obese ob/ob TG mice to exogenous leptin suggests that obese individuals with low leptin levels may respond well to treatment with exogenous leptin. This possibility awaits the outcome of clinical trials now underway.

Acknowledgments

Nosotros thank Susan Korres for proficient aid in preparing this manuscript.

Abridgement

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Articles from Proceedings of the National Academy of Sciences of the Us are provided here courtesy of National Academy of Sciences

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21729/

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