Lessons From Rodent Models of Obesity

Obese and Diabetes reveal the endocrine control of energy balance.

The obese (ob; now Lep^ob) mouse was identified as an autosomal recessive mutation in a noninbred strain (Stock V) at Jackson Laboratory in 1949 (6). Mice segregating for the obese gene were backcrossed for many generations to generate a congenic line on the C57BL/6J background strain. Lep^ob mice on C57BL/6J, despite their early-onset obesity and transient glucose intolerance, are not diabetic; however, the Lep^ob mutation coisogenic on the diabetes-prone C57BL/KsJ line results in severe, early-onset type 2 diabetes (22).

Diabetes (db; now Lepr^db) is a spontaneous recessive mutation that was first noted in a C57BL/KsJ mouse colony at the Jackson Laboratory. The KsJ Lepr^db mutant is hyperphagic and obese, but also develops severe type 2 diabetes (7). Backcrossing Lepr^db onto the C57BL/6J background attenuates the diabetic phenotype; C57BL/6J-Lepr^db is virtually identical to C57BL/6J-Lep^ob.

Douglas Coleman, at Jackson Labs, looking for the molecular predicates of the lipostatic system posited by Kennedy (23) and Hervey (24), performed parabiosis (joined circulation) studies coupling Lep^ob mice to either wild-type or Lepr^db mice (25). The Lep^ob mouse became lean when joined to a wild type, but, when joined to a Lepr^db mouse, the Lep^ob mouse died of starvation. These findings led Coleman to hypothesize that a blood-borne factor regulating body weight might be deficient in Lep^ob, but circulating at high levels in the blood of Lepr^db mice. He suggested that obese was the secreted factor and diabetes its receptor (25,26).

In 1994, the gene encoding Lep^ob was isolated by positional cloning (27) by a group at Rockefeller University, and its product, leptin, was shown to be produced primarily in adipocytes. Leptin is a type 1 cytokine, similar in structure to IL-6. Lep^ob mice lack circulating leptin by virtue of an R105X mutation that creates a premature stop codon sequence in the leptin gene, resulting in a truncated protein that is rapidly degraded (27).

The gene (Lepr) that encodes the receptor for leptin (LepR) was identified by expression cloning (28); the first genetic mutation in Lepr was identified in the Lepr^db mouse (10,29,30), thus confirming the conceptual model proposed by Coleman: the obesity of the Lepr^db mouse was due to a mutation that precluded leptin signaling by the receptor that binds the ob gene product.

Alternative splicing of the Lepr transcript produces multiple isoforms of the receptor (which is a cytokine receptor similar to members of the IL6 receptor family): LepRa, -b, -c, -d, and so forth (Figure 1). The mutation in the Lepr^db mouse results from a splicing defect that causes the 3′ terminal exon (18a) of leptin receptor isoform a (Lepr-a) to be inserted into Lepr-b. A stop codon at the end of exon 18a prevents transcription of the Lepr-b terminal exon, so that LepRa is produced in place of LepRb (10,29,30). Because the Lepr^db mouse synthesizes all leptin receptor isoforms except LepRb, it is clear that this isoform (which contains JAK box and STAT3 domains) is critical to the control of energy homeostasis (31). Indeed, restoration of LepRb on a background null for all other LepR isoforms restores energy balance (32).

Figure 1. LepR isoforms and function. LepRa (Ra) represents the mostly highly expressed short form of LepR; LepRb (Rb) is the long form. Exon 17 contains half of a Jak docking site (BOX1) common to Ra, Rb and Rc, while exon 18b contains additional motifs required for full Jak2 binding (BOX2) and STAT3 signaling (31,33). Circulating leptin binding protein consists of extracellular domain that has been cleaved from the cell surface, along with the LepRe splice variant that lacks a transmembrane domain. Humans do not generate the splice variant, so that all LepRe is produced by cell surface cleavage, presumably by membrane associated metalloproteases (33).

LepRa, -c, -d and the other so-called “short” isoforms contain the same first 17 exons as LepRb, but diverge within the intracellular domain. LepRb is the only isoform that mediates classical Jak-STAT signaling, as this isoform alone contains the motifs required to interact with Jak2 and to bind STAT proteins for downstream signaling (Figure 1)(34). While the function of LepRb is clear, the functions of the short isoforms are not, although they have been speculated to function in leptin transport into the brain and/or a source of cleaved, circulating extracellular LepR (which, along with LepRe comprises the major circulating leptin-binding protein) (35). The biological role(s) of soluble LepR isoforms (sLEPR) are unclear. Human obesity and fasting are associated with decreased circulating sLEPR; pregnancy with increased sLEPR. sLEPR can block LEP transport across the BBB(36-40).

The physiologic function of leptin.

Disruption of Lep function results in hyperphagia and obesity, and leptin administration to Lep^ob mice (but not Lepr^db animals), reduces food intake and adiposity, sparing lean tissue (41-43). Thus, Lep^ob and Lepr^db mice demonstrate that fat mass (along with both energy intake and expenditure) can be controlled by a single molecule. Leptin represents a powerful biologic controller of feeding and energy balance, revealing the existence of an endocrine system that controls feeding and energy balance. In humans, leptin deficiency also elicits a severe obesity phenotype: A rare, recessively inherited LEP mutation was discovered in two children who are members of a highly consanguineous Pakistani family (44). As with the Lep^ob mutation in mice, this frameshift mutation introduces a premature stop codon that truncates the leptin protein. While rare, additional leptin-deficient individuals (all of whom are severely obese) have been identified. Daily subcutaneous administration of recombinant leptin dramatically and selectively reduces body fat to normal levels in these individuals (45). A few humans homozygous for LEPR mutations have also been identified; these individuals present a severe obese phenotype similar to those lacking leptin, although – as anticipated - they are not responsive to exogenous leptin (46). In these patients, growth hormone deficiency and central hypothyroidism are phenotypes seen more frequently than in leptin deficiency per se. It is important to note that mice (47) and humans (48) heterozygous for null mutations of either LEPR or LEP are more obese than suitable controls. It is thus possible that individuals heterozygous for functionally null mutations of these and other genes encoding molecular components of the various signaling pathways regulating energy homeostasis discussed in this review constitute a significant proportion of the very obese. Additionally, heterozygosity for several of these mutations would be expected to produce even greater levels of obesity. The increasing use of exome sequencing in evaluating instances of severe obesity will lead to the detection of more instances of obesity caused by such oligogenic mechanisms.

While the role for leptin in the control of appetite and adiposity initially dominated the thinking about its biology, it rapidly became clear that leptin has other functions, and that the effects of high leptin are not as dramatic as those of low leptin. Indeed, obese rodents and humans exhibit high circulating concentrations of leptin, commensurate with their high levels of leptin-producing adipose tissue (49,50). Similarly, in contrast to the Lep^ob mice, increasing leptin to supraphysiologic levels in normal animals modestly and briefly blunts food intake and body weight [effect may be more striking than this]. Likewise, supraphysiological doses of leptin have only modest effects on body weight in obese and non-obese humans (51). Thus, the absence of leptin appears to convey a more powerful signal than does its excess. Also, Lep^ob mice (and their human counterparts) display additional phenotypes, including impaired growth and gonadal axis function, diminished immune function, infertility, and decreased energy expenditure due to low sympathetic nervous system tone and thyroid function- all of which are reversed by leptin treatment (52). The lack of leptin also promotes increased hepatic glucose production, and leptin treatment suppresses hyperglycemia in models of several diabetes, including T1D (53). This constellation of phenotypes resulting from low leptin mirrors the physiologic response to starvation; indeed, leptin treatment attenuates many of these consequences of very low adiposity (54). Thus, normal leptin concentrations signal the repletion of energy (fat) stores to mitigate hunger and enable energy expenditure, while low leptin indicates the dearth of adipose reserves and promotes food-seeking and the conservation of remaining fat by reducing energy expenditure. The concentration of leptin constituting such a signal of adequacy of fat stores may differ among individuals, reflecting genetic, developmental and acquired differences in the CNS molecules and circuits comprising this system (55).

Transgenic animals that lack adipose tissue exhibit a syndrome that mirrors that of lipodystrophic humans (who lack adipose tissue on a congenital or acquired basis): In spite of their leanness, lipodystrophic people and animals exhibit hyperphagia along with a predisposition to insulin resistance, diabetes and other endocrine and metabolic abnormalities that are not corrected even with caloric restriction (56,57). Due to their dearth of adipose tissue, leptin levels are low and leptin treatment improves their hunger and endocrine/metabolic abnormalities. Indeed, leptin was recently approved for the treatment of lipodystrophy syndromes in humans (58).

A leptin-regulated neural network underlies energy balance.

The similar phenotypes of Lep^ob and Lepr^db mice (along with the inability of leptin to alter physiology in Lepr^db mice) indicates that leptin action on LepRb-expressing cells must mediate its effects. Consistent with its behavioral effects (e.g., on feeding) and its effects on the neuroendocrine and autonomic systems, most LepRb-expressing cells lie in the brain. Indeed, transgenic overexpression of LepRb throughout the central nervous system (CNS) partially corrects the obesity syndrome of Lepr^db-3J mice (which lack all LepR isoforms) (32). Similarly, ablation of CNS LepRb using a neuron-specific Cre in combination with a floxed (Lepr^flox) allele promotes hyperphagia, neuroendocrine failure, and obesity (59). Some tissues outside of the CNS express LepRb, but the physiologic role for leptin action on these non-CNS cells remains unclear.

Within the brain, the majority of LepRb-expressing neurons are found within the hypothalamus and brainstem, consistent with the known roles for these structures in the control of feeding and endocrine and autonomic function (60-62). While LepRb ablation in the nucleus tractus solitarius (NTS) in the brainstem reduces satiety (consistent with the known role of this brain structure), pan-hypothalamic ablation of LepRb promotes a phenotype very similar in quality and magnitude to that of whole-body null Lepr^db animals (63). Furthermore, ablation of LepRb from broadly-distributed hypothalamic vGat- or Nos1-expressing neurons promotes dramatic hyperphagia and obesity (64,65). Smaller, more circumscribed sets of hypothalamic LepRb neurons have also been implicated, as well. Within the arcuate nucleus (ARC), an important satiety center in the brain, excision of Lepr^flox by Pomc^cre and Agrp^cre modestly increases feeding and adiposity (66,67). Ablation of LepRb in the SF1-expressing ventromedial hypothalamic nucleus (VMH) blunts the increase in energy expenditure that accompanies increased adiposity, and deletion of SF1 in the lateral hypothalamic area (LHA, which is associated with motivation) diminishes motor activity and promotes obesity (68,69). LepRb neurons in the ventral premammillary nucleus (PMv) play roles in reproduction (70). Importantly, many additional groups of LepRb cells in the hypothalamus (especially the ARC and dorsomedial hypothalamic nucleus (DMH)) and brainstem have as yet undetermined functions.

Spontaneously-arising Agouti mice reveal the crucial role for the hypothalamic melanocortin system in energy balance.

Expression of the agouti gene (a) normally occurs intermittently in the hair follicle resulting in the production of alternate yellow and black pigment bands of the resulting hair; this admixture produces the agouti coat color (71). The molecule acts as primarily as an inverse agonist at the melanocortin receptor (MC1R in skin).

The Yellow mutation of the agouti locus (A^y/a) is also termed ‘lethal yellow’, since homozygotes for the allele are prenatal lethal. Yellow was bred by mouse fanciers in Europe beginning in the 1800s, and was notable for the dominant inheritance of its striking yellow coat color and obesity proportional to the intensity of the yellow coat (5). In 1960, another spontaneous agouti mutation was detected in the Jackson Laboratory colony; viable yellow (A^vy) (72). The original, lethal, yellow mutation is a deletion of the Raly gene, which causes a fusion of the constitutively active Raly promoter to the agouti gene, resulting in ectopic continuous overexpression of agouti in all somatic (including brain) cells. A^vy/a is also the result of ectopic overexpression of agouti; this mutation results from insertion of a retrovirus-like repetitive intracisternal A particle (IAP) into a noncoding exon of agouti. The resulting splice variant fuses the constitutively active Raly promoter to the agouti gene, allowing constitutive overexpression of agouti in all somatic (including brain) cells.

The increased body weight of A^y/a and A^vy/a mice results mainly from hyperphagia, and reflects both increased fat mass and lean body mass (with increased body length) (73). By contrast, Lep^ob and Lepr^db mice have a selective expansion of fat mass due to increased food intake, decreased energy expenditure, preferential storage of excess calories as fat, decreased body length and lean body mass (74). Thus, agouti overexpression affects food intake similarly to leptin, but alters energy expenditure less dramatically.

The agouti gene encodes agouti signaling protein (ASP), a peptide with a high affinity for melanocortin receptors. The yellow coat color of the A^y/a mouse results from continuous overexpression of agouti in the skin which blocks (mainly by inverse agonist effects) alpha-melanocyte-stimulating hormone (a-MSH) signaling at melanocortin-1 receptors (MC1R) in the hair follicle (71,75). Since a-MSH activates melanocytes to initiate synthesis of eumelanin (black pigment) instead of phaeomelanin (yellow pigment), antagonism of a-MSH by ASP elicits a yellow coat color. ICV administration of a-MSH and a-MSH agonists decreases food intake and body weight; overexpression of agouti in the A^y/a brain antagonizes the anorectic action of a-MSH signaling as well as blunting the endogenous activity of the receptor, thus causing hyperphagia.

Fat reveals roles for peptide processing systems in the control of energy balance

Tubby.

The tubby mutation arose spontaneously at Jackson Laboratory in the C57BL/6 strain (9). These mice have a mild, late-onset obesity apparent by 8 to 12 weeks of age that is associated with hyperinsulinemia without hyperglycemia. Tubby results from a GàT transversion that interferes with normal intron excision (104). The result is an aberrant transcript in which a 44-base pair deletion at the 3′ end of the gene is replaced with a 24-base pair intronic segment that is usually spliced out. Tub^-/- mice are phenotypically indistinguishable from tubby, suggesting that the phenodeviant that occurred in the Jackson Laboratory colony had a loss-of-function mutation in the tubby gene. Lack of detectable tubby protein or transcript in tubby mice further supported this finding.

The precise physiological mechanism(s) underlying the obesity of tubby mice remain unknown (104), but the tubby mutation also produces retinal and cochlear degeneration, which is seen in primary ciliopathies such as the Bardet-Biedl and Alstrom syndromes. (See below). The tubby gene product, TUB, binds to membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) and is released upon PtdIns(4,5)P2 hydrolysis. A variety of data suggest an important role for TUB in GPCR signaling and trafficking, as well as insulin and leptin signaling, via the primary cilium (105).

Mahogany and mahoganoid.

The spontaneous, autosomal recessive coat color mutations, mahogany (mg) and mahoganoid (md), were first reported over forty years ago (71). When crossed to A^y/a mice, both mg and md darken coat color and attenuate obesity. Positional cloning of mg identified a gene orthologous to the human immune-response protein attractin (atrn), the gene product of which accumulates on the surface of activated T cells and subsequently facilitates the interaction between T cells and antigen by “attracting” macrophages (106). Atrn encodes a single transmembrane protein with a glycosaminoglycan side chain that has been suggested to chaperone agouti to melanocortin receptors. Atrn is expressed widely in the brain, as well as the skin, heart, kidney, liver and lung of wild-type mice. The Atrn^mg mutation in mice is due to a ~5-kb retroviral insertion in intron 11 that disrupts Atrn expression, and which permits a relative increase in eumelanin expression in the hair follicle, resulting in dark fur, presumably as a consequence of increased melanocortin signaling at the melanocortin-1 receptor (MC1R). Atrn^mg mutants also have 10-15% reduction in body weight and have 20-40% less body fat content than littermate controls. Deficiency of Atrn in A^y/a mice reduces body weight and adiposity by increasing energy expenditure rather than reducing food intake, suggesting melanocortin-independent mechanisms of action. Indeed, Atrn ^mg mice may have neurological deficits (107), and the zitter mutation, which causes hypomyleination in rats, results from an 8-bp deletion in Atrn at a splice donor site that decreases Atrn expression. Thus, Atrn function may not be entirely A^y/melanocortin-dependent.

The mahoganoid locus, Mgrn1 (mahogunin; RING finger 1), is located 2 cM from the centromere of chromosome 16 (108,109). Five mutations at this locus have been identified: md, md^3J, md^4J, md^5J, and md^6J. The Mgrn1^md mutation is a 5-kB IAP element intronic insertion between exons 11 and 12, which attenuates expression. Similar to the mg phenotype, the Mgrn1^md mouse is lean, and the allele reduces body weight and darkens the yellow coat color of A^y/a mice. The Mgrn gene product contains a RING finger domain consistent with ubiquitin E3 ligase function. Although the spontaneous mutations at the Mgrn1 locus do not cause neurological degeneration, the Mgrn1^md-nc mutation generated by caffeine mutagenesis results in histopathological changes similar to those seen in Atrn^mg and the zitter rat (110). Both mahoganoid and mahogany convey their effects on ASP signaling by effects on endosomal trafficking of MC4R (111).

Hypothalamic circuits important for energy balance

Reward circuitry

Genes involved in insulin and leptin signaling.

Mouse Models of human obesity syndromes.

Systemic immune signaling promotes negative energy balance.

Lipopolysaccharide (LPS) administration, which produces some of the metabolic consequences of bacterial infection, blunts appetite; the mechanism of this hypophagia overlaps with the systems that control energy balance, as the LPS-induced anorexia requires the melanocortin system (220). Consistent with the induction of negative energy balance by systemic inflammation, alterations that blunt inflammation generally blunt inflammatory anorexia. While not altering baseline energy balance in chow-fed animals, deletion of IL-1b converting enzyme (ICE; which is essential for IL-1b activity), prevents LPS-induced anorexia in mice (221). The inflammatory system may also contribute to the control of energy balance under normal physiology, as well: adiposity is increased in Il6^-/- and Gmcsf^-/- mice, and in mice with impaired macrophage function due to the targeted deletion of Mac-1 or LFA-1 (or their receptor, ICAM-1) (222). Conversely, mice with constitutively increased IL-1 receptor signaling induced by targeted deletion of the endogenous IL-1 receptor antagonist, Il1ra, display reduced body mass compared to wild-type littermates (223).

Metabolic inflammation.

Obesity is associated with increased production of a number of cytokines (including TNFa) in adipose tissue, resulting primarily from the activation of adipose tissue macrophages and other immune cells (224,225). Indeed, a number of manipulations that decrease adipose tissue inflammation ameliorate the metabolic dysfunction associated with obesity. While interference with generalized macrophage function may increase adiposity, as noted above, other manipulations that alter their pro-inflammatory (versus anti-inflammatory) nature increase leanness and improve metabolic function (226,227). Similarly, interfering with the Nf-kb pathway (which is crucial for the response to a variety of inflammatory stimuli) in the liver improves metabolic function in obese mice. Some data also suggest a contributory role of hypothalamic inflammation, including gliosis, in promoting obesity. However, debate continues regarding whether this inflammation provokes or attenuates obesity, virus-mediated interference with Nf-kb signaling in the hypothalamus ameliorates obesity and metabolic dysfunction (228). The ER stress in adipose tissue and the hypothalamus, potentially a consequence of metabolic inflammation, is also associated with obesity (229). Genetic or pharmacologic interference with ER stress ameliorates obesity and insulin resistance in rodent models.

Animal models with altered energy expenditure.

Uncoupling protein 1 (UCP1, which is found primarily in brown and beige adipose tissue (BAT)) allows dissipation of the electrochemical gradient across the inner mitochondrial membrane, releasing energy as heat (230). Ablation of BAT in mice expressing diphtheria toxin A driven from the UCP1 promoter or congenital deletion of Ucp1 fails to alter adiposity at thermoneutrality, although adiposity increases slightly relative to controls in animals raised at temperatures colder than thermoneutrality, since these animals fail to substantially increase energy expenditure in response to the cold challenge (231). Similarly, the phenotype of mice null for the b₃-AR was not as severe as predicted: fat mass in male mice is only slightly increased, even in animals consuming a high-energy diet under non-thermoneutral conditions (232). Also, “b-less” mice, with a global targeted deletion of all three b-adrenergic receptor isoforms, have only slightly increased body fat (22.2 % ± 0.9 as compared to 16.2% ± 1.9 for wild type controls) on high fat diet under non-thermoneutral (232).

Increased sympathoadrenal activity in adipose tissue activates a signaling cascade that induces phosphorylation of regulatory subunits of protein kinase A (PKA), which in turn inhibits lipogenesis and increases lipolysis. Deletion of the regulatory subunit II b of PKA (RII b ) , found mainly in WAT, BAT and brain, causes a compensatory increase in RI a , a subunit isoform that constitutively upregulates PKA activity (233). RII b -/- mice therefore have constitutively increased cAMP in response to sympathetic activation in adipose depots, with secondary elevation of metabolic rate and body temperature, and a 50% reduction in WAT pad weight despite a compensatory hyperphagia.

Glucocorticoids and adipocyte 11-β–hydroxysteroid dehydrogenase type 1 (11βHSD-1).

11βHSD-1 is the enzyme that catalyzes the conversion of cortisone to biologically active cortisol. Visceral obesity is associated with elevated cortisol secretion due to increased local activity of 11βbHSD-β1 in adipose tissue, but normal levels of circulating glucocorticoids (234). Transgenic overexpression of 11βHSD-1 driven by the aP2 promoter (to confer adipose tissue specificity) produced mice that consumed 17.1% more calories than lean controls and thus gained 16% more weight by 9 weeks of age, and weighed 21% more calories than controls when administered a high-fat diet. A 3.7-fold increase in the mesenteric (visceral) fat pad weight was detected (235). These findings suggest that increased production of glucocorticoids in adipose tissue drives the visceral obesity syndrome, although the increased food intake in these animals implicates potential non-local mechanisms.

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