Emerging Therapeutic Strategies for Obesity

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Emerging Therapeutic Strategies for Obesity

• Endocrine Reviews, December 2006, 27(7)779793
• Karen E. Foster-Schubert and David E. Cummings
• 96/03/23
• ???

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Introduction

• The rising tide of obesity is one of the most
  pressing health issues of our time, yet existing
  medicines to combat the problem are
  disappointingly limited in number and
  effectiveness.
• Fortunately, a recent burgeoning of mechanistic
  insights into the neuroendocrine regulation of
  body weight provides an expanding list of
  molecular targets for novel, rationally designed
  antiobesity pharmaceuticals.

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• In this review, we articulate a set of conceptual
  principles that we feel could help prioritize
  among these molecules in the development of
  obesity therapeutics, based on an understanding
  of energy homeostasis.
• We focus primarily on central targets,
  highlighting selected strategies to stimulate
  endogenous catabolic signals or inhibit anabolic
  signals.

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I. The Obesity Crisis

• The National Institutes of Health recommend
  pharmacotherapy, in conjunction with lifestyle
  modification, for all obese individuals (i.e.,
  body mass index 30 kg/m2) and for overweight
  persons with a body mass index greater than 27
  kg/m2 accompanied by at least one comorbidity .

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• Given the startling prevalence of overweight and
  obesity, this policy mandates pharmacotherapy for
  approximately half of all American adults.
• Yet only three medicationssibutramine,
  phentermine, and orlistatare approved in the
  United States to treat obesity, and each of these
  typically promotes no more than 510 loss of
  body weight.

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II. Neuroendocrine Regulation of Body Weight

• Despite marked fluctuations in daily food intake,
  body weight remains remarkably stable in most
  humans because overall energy intake and
  expenditure are exquisitely matched over long
  periods of time through the process of energy
  homeostasis.
• In response to alterations of body adiposity,
  the brain triggers compensatory physiological
  adaptations that resist weight change.
• Specifically, weight loss increases hunger and
  decreases metabolic rate, whereas weight gain
  elicits the opposite responses.

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• FIG. 1. Model depicting how changes in body
  adiposity elicit compensatory alterations in food
  intake and energy expenditure. Leptin and insulin
  are adiposity-associated hormones that are
  secreted in proportion to body fat content. They
  act in the hypothalamus and other brain sites to
  stimulate catabolic neural pathways while
  inhibiting anabolic pathways. This endocrine
  negative feedback system influences energy
  balance (the difference between calories ingested
  and expended) to regulate body adiposity.

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III. Principles for the Design ofAntiobesity
Therapeutics

• Living organisms obey the first law of
  thermodynamics,and their body weight depends
  ultimately upon the balance between energy intake
  and output.
• Consequently, three broad strategies to promote
  weight loss are to stimulate anorexigenic
  signals, oppose orexigenic signals, or increase
  energy expenditure, and all of these approaches
  are under active investigation.

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• First, because the energy homeostasis system is
  highly redundant, antagonism of anabolic signals
  is theoretically limited in its ability to
  promote major weight reduction because changes in
  other pathways could compensate for the loss of a
  pure orexigen.
• Second, weight loss resulting from an
  intervention that only stimulates metabolic rate
  should elicit an adaptive increase in food
  intake. Even if the elevation in energy
  expenditure is so great that it supersedes
  compensatory hyperphagia, the result would be
  weight loss occurring at the expense of excessive
  caloric turnover.

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• Third, because body weight is defended by
  redundant regulatory systems, combination
  therapies targeting more than one pathway might
  be required to promote clinically meaningful
  weight loss.
• Lastly, the remarkably sophisticated current
  understanding of adipocyte biology could
  facilitate development of agents that entirely
  obliterate fat tissue, and although this might
  seem intuitively desirable for people with excess
  adiposity, significant evidence suggests that
  such approaches would be deleterious.

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IV. Stimulators of Catabolic Pathways

• Of the 11 known genes that can cause monogenic
  obesity in humans, at least seven encode
  catabolic proteins that lie in the
  leptin-melanocortin circuit specifically,
  leptin, leptin receptor, POMC, prohormone
  convertase 1, melanocortin 3 and 4 receptors, and
  singleminded 1 (SIM1).
• Thus, compelling experiments of nature identify
  this pathway as a high-priority target for
  antiobesity pharmaceuticals.

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• A. Leptin and leptin-receptor agonists
• B. Strategies to overcome obesity-related leptin
  resistance
• C. Second- and higher-order targets of leptin
  actionmelanocortins
• D. Ciliary neurotrophic factor
• E. Subtype-selective serotonin-receptor agonists

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A. Leptin and leptin-receptor agonists

• The extraordinary obesity phenotype that results
  from leptin deficiency distinguishes leptin as
  probably the single most important molecule in
  mammalian energy homeostasis.
• Because it is the kingpin hormone in an endocrine
  negative-feedback loop limiting body weight,
  scientists initially hoped that exogenous
  administration would ameliorate obesity.
• Indeed, among rare individuals who are obese
  because they lack leptin, physiological
  replacement is curative.

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• Common obesity, however, is associated with high
  levels of leptin, proportionate to adipose
  stores, but obese individuals show a blunted
  response to the catabolic effects of these high
  levels.
• Hence, common obesity is a state of leptin
  resistanceresistance so resolute that exogenous
  administration of even extremely high doses of
  leptin has thus far proven relatively ineffective
  at reducing body weight in this setting.

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B. Strategies to overcome obesity-related leptin
resistance

• Leptin resistance results from impairments in
  leptin action at multiple levels, and each of
  these could theoretically be targeted to overcome
  leptin insensitivity in obese individuals.
• First, leptin is normally transported across the
  blood brain barrier by a saturable system
  involving a specialized leptin-receptor isoform,
  and this transport mechanism is impaired in
  obesity.

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• Recent evidence suggests that intranasal delivery
  of leptin can overcome this barrier and cause
  weight loss.
• Leptin delivered to the nares of rats generated
  supraphysiological levels in the brain,
  especially, and importantly,in the hypothalamus.
• This effect was not diminished when circulating
  leptin levels were raised by concomitant iv
  administration.

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• Leptin receptor activation engages two
  intracellular proteins that terminate receptor
  signalingnamely, suppressor of cytokine
  signaling-3 (SOCS3) and protein tyrosine
  phosphatase- 1B (PTP1B)and inhibition of either
  of these autoinhibitory factors could
  theoretically increase leptin sensitivity.
• This strategy is particularly compelling for
  SOCS3 because its activity is increased in
  obesity, suggesting an etiological role in leptin
  resistance .

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• PTP1B inactivates the leptin receptor by
  dephosphorylating key tyrosine residues that are
  phosphorylated in response to ligand binding.
• Thus, analogous to SOCS3, inhibition of PTP1B
  should increase leptin sensitivity.
• Moreover, because PTP1B also limits
  insulin-receptor signaling, inhibiting it might
  increase insulin sensitivity independent of its
  effects on body weight.

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C. Second- and higher-order targets of leptin
action melanocortins

• Because obesity-related leptin resistance occurs
  at least partly at the level of leptin gaining
  access to and activating its first-order neuronal
  targets in the hypothalamus (e.g., POMC and
  NPY/Agrp neurons), a logical strategy is to
  manipulate leptin-regulated pathways distal to
  these neurons.

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• Of the many such pathways, the leptin-melanocortin
  system provides particularly appealing targets
  because of the observation that monogenic obesity
  phenotypes result from mutations in genes at
  multiple levels throughout this circuitry.
• In addition to activating the melanocortin
  pathway, leptin also stimulates other
  second-order hypothalamic anorectic mediators,
  such as TRH and CRH but these are not very
  appealing antiobesity drug targets because of
  their critical roles in thyroid and adrenal
  regulation, respectively.

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• In the leptin-melanocortin pathway, POMC is the
  first key intermediary downstream of
  leptin-receptor signaling.
• Genetic evidence in rodents and humans reveals
  an indispensable role for this gene product in
  body-weight regulation, and even
  haploinsufficiency is associated with obesity.
• Pharmacological mechanisms to increase POMC
  expression are not apparent, however, and even if
  this could be achieved, it would likely cause
  undesirable additional effects, given the
  involvement of POMC-derived peptides in adrenal
  physiology and other functions.

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D. Ciliary neurotrophic factor

• Ciliary neurotrophic factor (CNTF) is a glial
  cell-produced cytokine that exhibits
  neuroprotective effects and has therefore been
  explored as a medicine to treat neurodegenerative
  diseases.
• Unexpectedly, subjects receiving CNTF in clinical
  trials for this indication experienced a 1015
  weight loss, prompting investigators to consider
  using CNTF to treat obesity.
• The exact mechanisms mediating these catabolic
  effects are unclear, although it is known that
  they do not result from cachexia or muscle
  wasting.

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• Moreover, unlike leptin, CNTF causes weight loss
  independent of melanocortins and is effective in
  mice lacking either POMC or Mc4r, both of which
  are required for leptins full anorectic effects.
  
• Importantly, CNTFalso reduces body weight in
  animals with leptin resistance resulting from
  diet-induced obesity , suggesting that it might
  be clinically efficacious in this setting.
• Although CNTF does not require leptin signaling,
  its own cytokine receptor, which is expressed in
  the hypothalamus, has signal transduction
  elements and activates intracellular signaling
  pathways similar to those of the leptin receptor
  .

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E. Subtype-selective serotonin-receptor agonists

• Three of the medicines that have been used
  clinically to treat obesitysibutramine,
  fenfluramine, and dexfenfluramine (d-FEN)all
  increase signaling by the neurotransmitter
  serotonin 5hydroxytryptamine (5-HT).

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• Further studies identified a complementary role
  for the 5-HT1B receptor in feeding regulation .
• Activation of this receptor on arcuate NPY/Agrp
  cells inhibits neuronal activity, thereby
  derepressing the inhibitory GABAergic
  transmission from NPY/Agrp neurons to adjacent
  POMC neurons.
• Evidence from a limited number of clinical
  studies examining the use of isoform-selective
  5-HT receptor agonists as anorectic agents
  appears to confirm that stimulation of 5-HT2C,
  and possibly 5-HT1B, reduces hunger, food intake,
  and body weight in humans.

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V. Inhibitors of Anabolic Neuropeptides

• A. Neuropeptide Y and its many receptors
• B. Melanin-concentrating hormone

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A. Neuropeptide Y and its many receptors

• In addition to stimulating melanocortins and
  other catabolic pathways, the adiposity hormones
  leptin and insulin inhibit anabolic
  neuropeptides, such as hypothalamic NPY, and
  chronic NPY administration powerfully increases
  food intake and body weight.
• Thus, pharmacological blockade of NPY signaling
  is a potential antiobesity strategy.

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B. Melanin-concentrating hormone

• Another leptin-inhibited orexigenic hypothalamic
  neuropeptide is melanin-concentrating hormone
  (MCH).
• Exclusively expressed in magnocellular neurons of
  the lateral hypothalamic area, this peptide acts
  downstream of at least some levels of leptin
  resistance, and thus it represents another
  logical option for obesity pharmacotherapy.
• Furthermore, both gain- and loss-of-function
  experiments demonstrate an important role for MCH
  in body weight regulation.

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• Medicinal blockade of MCH signaling is being
  explored as an antiobesity modality. Because this
  would be achieved with antagonists of MCHR1, mice
  lacking the MCHR1 gene theoretically represent a
  better model than MCH knockouts to help predict
  the impact of such pharmacotherapy.

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VI. Gastrointestinal Peptides That RegulateFood
Intake

• A. Glucagon-like peptide-1
• B. Peptide-YY
• C. Oxyntomodulin
• D. Amylin
• E. Ghrelin

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A. Glucagon-like peptide-1

• Three peptides released from lower intestinal L
  cells in response to ingested nutrientsglucagon-l
  ike peptide-1 (GLP-1), peptide-YY (PYY), and
  oxyntomodulinare believed to act in concert with
  other postprandial GI signals (e.g., gastric
  distention, cholecystokinin, etc.) to cause
  satiation, promoting meal termination .
• All three of these L cell products have been
  shown to decrease food intake and body weight in
  experimental animals and to exert anorectic
  effects in humans.

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• The protease-resistant GLP-1 congener exenatide
  is already marketed to treat diabetes because it
  increases insulin secretion and possibly
  sensitivity.
• In clinical trials, exenatide reduces hemoglobin
  A1C at least as well as do other oral diabetes
  agents, while also causing a modest but
  progressive weight loss that persists for at
  least 2 yr.
• The mechanisms mediating anorectic effects of
  GLP-1 are not fully known but appear to involve
  an important role for the vagus nerve.

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B. Peptide-YY

• Peripheral administration of PYY can reduce food
  intake and body weight in rodents, apparently by
  activating autoinhibitory Y2 receptors on
  orexigenic NPY/Agrp neurons in the hypothalamus,
  and thereby derepressing adjacent
  anorexigenicPOMCneurons.

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• Although the catabolic effects of peripheral PYY
  are somewhat subtle and subject to vicissitudes
  of experimental conditions in rodents , these
  effects may be more robust in primates , and PYY
  administration in humans has been reported to
  lessen hunger and decrease single-meal food
  intake by 36, without eliciting illness or
  subsequent compensatory hyperphagia .

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C. Oxyntomodulin

• Chronic oxyntomodulin injections in animals
  decrease body weight more than expected from the
  reduction in food intake, suggesting an
  additional effect from increased energy
  expenditure.
• In humans, iv oxyntomodulin infusions acutely
  decrease hunger and single-meal food intake,
  without reducing food palatability.

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D. Amylin

• Amylin, a peptide cosecreted with insulin
  postprandially from pancreatic -cells, inhibits
  gastric emptying, gastric acid output, and
  glucagon secretion.
• It can also dose-dependently decrease meal size
  and food intake, through vagus-independent
  actions on the hindbrain area postrema.
• The synthetic amylin analog pramlintide is
  marketed for diabetes treatment, but it also
  causes mild progressive weight loss for at least
  16 wk in humans.

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E. Ghrelin

• Ghrelin, the only known orexigenic hormone, is
  released from the stomach and upper intestine
  shortly before individual meals and is rapidly
  suppressed by food intake .

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• Moreover, ghrelin appears to play a role in
  long-term body-weight regulation, based on the
  following observations
• 1) circulating ghrelin levels display
  compensatory responses to changes in body weight,
  rising with weight loss and vice versa
• 2) ghrelin enters selected brain areas and acts
  through its receptor to modulate neuronal
  activity in classical centers of energy
  homeostasisincluding the hypothalamus, caudal
  brainstem, and mesolimbic reward nodesand
  ghrelin injections in any of these sites potently
  stimulate food intake
• 3) chronic or repeated ghrelin administration
  increases body weight in experimental animals and
  humans through anabolic effects on numerous
  aspects of energy intake, energy expenditure, and
  fuel utilization.

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VII. Bringing It All Together Cannabinoid-1Recep
tor Antagonism

• Among the many novel antiobesity strategies
  currently under development, pharmacological
  antagonism of the anabolic cannabinoid-1 receptor
  will probably be the first to come into clinical
  use.

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• That CB1R might play an important role in
  body-weight regulation is implied by the fact
  that it is selectively expressed in virtually
  every major site in the energy homeostasis system
  .
• In the brain, CB1R is abundant and widely
  distributed, including in vital energy-regulatory
  centers such as the hypothalamus, caudal
  brainstem, and mesolimbic reward nodes.
• In the periphery, CB1R is found primarily in the
  GI tract, adipose tissue, liver, muscle, thyroid,
  and pancreasall of which contribute importantly
  to energy balance.

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The End

• Thank you for your attention