Adipobiology (The Study of Fat in the Body): An Emerging Field

What exactly does stored fat do to a horse's body? It wreaks serious havoc on at least 11 vital body functions. Nat Messer, DVM, Dipl. ABVP, an associate professor of equine medicine and surgery at the University of Missouri (UM), presented a compelling discussion of the relatively new field of adipobiology--the study of fat and its causes and effects. He discussed a paper submitted by Philip Johnson, BVSc(Hons), MS, Dipl. ACVIM, Dipl. ECEIM, MRCVS, professor of veterinary medicine and surgery at UM.

Excess body fat (both subcutaneous fat, such as the squishy stuff around a horse's tailhead, and visceral fat that accumulates near various internal organs) isn't just an unsightly way to store extra calories. Researchers are learning that fat--or adipose tissue as it's scientifically called--is much more active biochemically in many species than was previously thought (particularly visceral fat), noted Johnson in his paper. Fat produces more than 100 substances (collectively called adipokines or adipocytokines) that can affect:

  • Lipid and glucose homeostasis (normal fat and glucose balance in the body);
  • Inflammation;
  • Hemostasis (control of bleeding);
  • Osteogenesis (bone production);
  • Hematopoiesis (formation and development of blood cells);
  • Complement activities (complement is a sequence of proteins in the blood that work to help the animal respond to inflammatory and infectious challenges);
  • Reproduction;
  • Angiogenesis (development of blood vessels in tissue);
  • Blood pressure; and
  • Feeding behavior.

In horses, adipokine-mediated alteration of these body functions can cause or contribute to chronic inflammation, metabolic problems such as insulin resistance and possibly pituitary pars intermedia dysfunction (Cushing's disease), circulatory (blood vessel) compromise, and increased risk of laminitis. Also, hyperglycemia (high blood sugar, which is common in horses with severe metabolic syndrome) has been shown to generate oxidative stress--the production of oxygen free radicals that can damage many kinds of tissues.

"In fact, adipokines have recently been claimed to represent the 'missing link' between IR (insulin resistance) and cardiovascular disease in humans," said Johnson. For example, he noted that the branch of the coronary artery passing through an area of fat storage is the one most likely to develop arthrosclerosis (progressive narrowing and hardening of the artery, which can lead to a heart attack or stroke). Local effects of hormones produced by that fat deposit have been implicated as the cause.

Obesity and Insulin Resistance

Even if a horse is fat, if he is insulin- resistant, the cells in his body that depend on insulin for glucose uptake (generally skeletal muscle cells, as well as liver and fat cells) are actually starved for energy--the glucose they should be getting from food metabolism. "Decreased movement of glucose into the cell through glucose transporters (GLUT-4 in this case) in the cell membrane ... is the first step that is defective in human insulin resistance," explained Johnson. This can occur when fatty acids in skeletal muscle directly inhibit insulin activation of glucose-transport activity, he noted.

Not all obese horses develop insulin resistance, and not all insulin-resistant horses are obese, noted Messer. "But IR- associated medical problems are more likely to develop in concert with obesity in individuals born with IR," he said. "Obesity may be an 'add-on' risk factor."

Obesity and Laminitis

"Compelling experimental data have been published to suggest that glucose is essential for the health and strength of the equine hoof-lamellar interface," noted Johnson. "Hemidesmosomes (HD) represent the important attachment link between keratinocytes (hoof wall cells) and the underlying lamellar basement membrane (attaching the coffin bone to the hoof wall). Keratinocyte glucose starvation (from the aforementioned decreased movement of glucose into the cells) may weaken HD, which leads to separation of the keratinocyte from the basement membrane. Situations associated with cell- glucose starvation, such as IR, might increase the risk for laminitis."

He noted that it remains to be seen whether hoof keratinocytes depend (to any extent) on insulin for their glucose supply; this information is currently unknown.

In obese horses insulin resistance might also contribute to widespread inflammation and, thus, vasoconstriction (narrowing of the blood vessels), which is the case in human metabolic syndrome, Johnson added. "By so doing, IR may, in turn, promote the risk of laminitis. The equine hoof-lamellar microvasculature is extremely sensitive to vasoconstrictors (anything that constricts blood vessels)," he explained. Therefore, adipokine-induced vasoconstriction would pose another pathway for causing laminitis in obese horses.

Glucocorticoids and Obesity

Additionally, glucocorticoids have been implicated as a cause of both laminitis and IR. "Our team has been interested in the role that glucocorticoids (corticosteroid drugs or hormones that are involved in carbohydrate metabolism and the body's response to stress) might play in terms of risk of laminitis," Johnson commented. "Newer work in humans suggests that glucocorticoids play a critical role in the development of visceral obesity and metabolic syndrome.

"Glucocorticoids also cause expansion of adipose tissues in the body," he noted. "If present in sufficient quantity (as in the obese state), locally generated cortisol (often called stress hormone) will both stimulate further local adipogenesis (fat deposition) and contribute to IR.

"Circumstances under which individuals might be influenced by the action of excess glucocorticoids include Cushing's syndrome, the administration of synthetic glucocorticoids for therapeutic purposes, and stress," he wrote.

Treating Obesity

Unfortunately, "Obesity in horses is often desirable to owners," said Messer.

"There clearly exists a need for objective criteria by which horses might be 'scored' in terms of whole-body adiposity (such as the body mass index used in human medicine)," Johnson noted.

He added that a major goal of adiposity research focuses on identifying therapeutic strategies that effectively reduce the ratio of pro-inflammatory (inflammation- causing), insulin-desensitizing adipokines to anti-inflammatory, insulin-sensitizing adipokines. Owners need to control obesity now by properly managing horses' diets and increasing exercise levels.

Messer summarized his presentation quite succinctly: "You've seen what fat cells can do today. Until we get rid of excessive fat cells, we'll have all kinds of problems."

Obesity and Insulin Resistance

Nicholas Frank, DVM, PhD, Dipl. ACVIM, associate professor of large animal clinical sciences at the University of Tennessee, discussed the causes, clinical signs, and management of insulin resistance in horses, and its link to laminitis.

"Insulin resistance can be defined as failure of tissues to respond appropriately to insulin," said Frank. "Insulin is secreted by the pancreas to move glucose (sugar from digestion of food) into tissues when it's readily available (after meals)."

There are three types of insulin resistance. "Compensated IR is the most common form; this is when the pancreas secretes more insulin to achieve the same effect (hyperinsulinemia)," he explained. "Uncompensated IR is when pancreatic beta cells (the source of insulin) fail, so blood glucose concentrations rise and insulin levels are variable; this is fairly rare. An extremely rare event is Type 2 diabetes mellitus (caused by insufficient production of insulin or by resistance of target tissues to the effects of insulin), which describes advanced pituitary pars intermedia dysfunction (PPID, or Cushing's). This results in hyperglycemia (high blood sugar) and glucosuria (sugar in the urine)."

Insulin resistance is a part of equine metabolic syndrome (EMS). Said Frank, "There are three criteria for identifying the horse with EMS: Insulin resistance, prior (founder lines) or current laminitis, and general obesity or regional adiposity (areas of abnormal fat deposition such as a cresty neck or fat pads near the tailhead). It has a genetic predisposition--the 'easy keeper,' or the horse that could stay fat on fresh air, is more likely to have EMS."

Insulin Resistance and Laminitis

There are three theories on why insulin resistance might contribute to laminitis:

1. It decreases the amount of glucose getting into hoof tissue cells, which could starve them and hamper their function.

2. Insulin resistance causes decreased peripheral vasodilation (contraction of blood vessels at the extremities, such as in the hoof). Decreased blood flow to the foot means less nutrition for the tissues and likely less healthy tissues.

3. When adipose tissues reach their capacity for fat storage, they can become stressed and release cytokines, causing a pro-inflammatory state. This could lower a horse's threshold for laminitis. Thus, a smaller trigger could cause laminitis--less of a carbohydrate overdose, for example.

Whatever its mechanism of action might be, insulin resistance has been linked to laminitis. Frank described a study of a Virginia pony herd that found insulin sensitivity could even predict laminitis: "Measuring their insulin sensitivity predicted laminitis would occur in 13 ponies, and it actually developed in 11 (85%). This was the first paper saying insulin sensitivity had something to do with laminitis."

The Role of Obesity in IR

"Not all obese individuals are insulin- resistant, and not all IR-affected horses are obese. But IR-associated medical problems are more likely to develop in concert with obesity in individuals born with IR," said Messer. "Thus, obesity may be an 'add-on' risk factor," much as obesity in humans contributes to diabetes.

"The obese 'easy keeper' is poorly defined scientifically," Frank said. "Presumably this characteristic is inherited as a difference in metabolism where the horse is able to maintain weight on fewer calories--he's evolutionarily adapted to live on less food in harsh conditions. When you take this adapted horse and put him on a high-carbohydrate diet (including good pasture), he tends to become obese. Grain can make it even worse.

The theory of how obesity contributes to insulin resistance is as follows, he said: "The accumulation of lipids (fat molecules or diacylg lycerol) in cells alters the normal signaling events within the cell. Skeletal muscle is the most susceptible to this. The theory is that as animal gets more obese, intracellular lipids interfere with insulin activity. Insulin resistance develops as lipids disrupt insulin receptors. Initially this is a reversible process, but chronic IR causes irreversible damage."

Hold the Grain, Please

Management of insulin resistance might lower the risk of laminitis, and one of the cornerstones of management is diet. "Think of these horses as being in a prediabetic state," Frank said. "They need to exercise more and take in less sugar."

He made these recommendations:

  • Take obese horses off sweet feed, they don't need it anyway.
  • Consider a grazing muzzle.
  • Don't overfeed them.
  • Feed hay lower in nonstructural carbohydrates (NSC; forage testing labs can tell you a hay's NSC content).
  • Induce weight loss by feeding hay initially at 2% of the horse's current body weight, decreasing to 1.5% of current body weight, then finally dropping to 1.5% of ideal body weight.
  • Consider pergolide treatment in horses with EMS to stave off PPID.
  • Exercise horses to decrease weight.

If an insulin-resistant horse develops laminitis, Frank recommended the following management practices:

  • Take the horse off pasture entirely-- remove some horses permanently, but most temporarily.
  • Keep the horse in a dry lot.
  • Hand-walk him for exercise once his feet are stabilized.
  • If he's obese, feed low-sugar hay.
  • If he's lean, feed hay plus a low-NSC feed.
  • Consider strategic use of levothyroxine (generally used as replacement therapy in reduced or absent thyroid function) for three to six months in obese horses. However, "We are not treating hypothyroidism!" he stated. "That condition is extremely rare in horses. We are using it to accelerate metabolism (to decrease body weight)."

Frank said in an ongoing study, horses in a dry lot and given levothyroxine (Thyro-L; Lloyd Inc., Shenandoah, Iowa) lost an average of 62 kg, compared to 25 kg lost by horses in a dry lot without evothyroxine.

Take-Home Messages

The following facts should be considered if you have a horse that is showing signs of becoming overweight or having insulin resistance.

  • Not all obese horses have EMS, and not all horses with EMS are obese.
  • Diet and exercise are the main management and prevention strategies. Owners should avoid feeding concentrates and control affected or at-risk horses' exposure to pasture.
  • Levothyroxine can be given to reduce body weight and increase insulin sensitivity for three to six months.

Cushing's Disease: Challenges of Diagnosis and Treatment

We know Cushing's disease (or pituitary pars intermedia dysfunction--PPID--as it's more scientifically called), simply put, is an "old-horse disease" that results in metabolism disturbances and an abnormally heavy hair coat. But when it comes to testing and treatment, there are about as many opinions as there are people to ask. Luckily, Harold Schott, DVM, PhD, Dipl. ACVIM, professor of large animal clinical sciences at Michigan State University (MSU), discussed the challenges of PPID diagnosis and treatment.

"Owners have really pushed us to learn more about this disease," he began. "Unfortunately, I might not leave you with a totally clear picture, because a lot of what we know is still based on experience rather than scientific data."

Pituitary pars intermedia dysfunction describes altered activity of the pars intermedia lobe of the pituitary gland. Schott first described the prevalence of PPID clinical signs seen in various studies: hirsutism (excessive haircoat) 47-100% of affected horses; muscle wasting, 35-88%; chronic laminitis, 24-82%; polyuria/polydipsia (excessive urination and chronic, excessive thirst/intake of fluid), 17-76%; hyperhidrosis (excessive sweating), 14-67%; abnormal fat deposition, 9-67%; chronic infections, 27-48%; lethargy, 43-82%; neurological signs, including seizures, 6-50%

"My subjective impression is that age at onset of clinical signs is important; the younger ones (at onset) do worse," said Schott.

"Laminitis is the clinical problem we deal with the most," he commented. "It's our main reason for looking at these horses. Here's take-home message #1: Evaluation for PPID is warranted in horses more than 15 years old that develop insidious (gradual) onset laminitis."

Diagnosing PPID

Unfortunately, no perfect PPID test (one that is 100% accurate with a single-sample test) yet exists. Schott noted that 11 tests are possible, from simple evaluation of clinical signs ("over-the-fence" diagnosis of hirsutism) to various measures of hormone levels in blood plasma and urine.

"The dexamethasone suppression test (DST) is considered by many to be the gold standard diagnostic test, probably because of experience with it rather than actual data," he commented. "It's the most widely accepted test, the samples are stable (less affected by variations in handling), and cortisol measurement is readily available (at labs)."

The test is based on the fact that one pituitary pars intermedia hormone product stimulates the adrenal glands to produce excess cortisol (often termed stress hormone).

Schott explained that the DST involves measuring cortisol, giving the horse dexamethasone (a steroid analogue that is used in this case to suppress cortisol stimulation from another lobe of the pituitary gland) in the late afternoon, then measuring plasma cortisol the next morning (15 and 19 hours after dexamethasone administration). Cortisol levels greater than 1 ug/dL at those times support a diagnosis of PPID.

Disadvantages: The DST requires three client visits (although the test can be modified to two visits), it is reported to exacerbate laminitis in rare cases (although Schott noted this observation is poorly documented), its results are not always repeatable, and it might miss early PPID.

He briefly discussed several other hormone tests and their accuracy levels, noting that researchers are finding significant seasonal variation in hormone levels and, thus, seasonal variation in test results, even on the same horses.

"Take-home message #2 is that seasonal variation complicates diagnostic testing--endocrine testing is not recommended from mid-August to mid-November because we have difficulty interpreting the results," he cautioned.

In addition to hormone testing, researchers often will evaluate pituitary gland tissue of research horses post-mortem to try to correlate histological (tissue) characteristics with hormone test results and clinical signs. Schott described a study that found lesions were common in both the pars intermedia and pars distalis regions of the pituitary gland. There was one other notable feature of the horses that were examined--they were all clinically normal.

"Based on this ('abnormal' tissue findings in horses that had no clinical signs of disease), I'm not sure histological examination is the way to go," he opined. "Take-home message #3 is that hirsutism is still the most accurate diagnostic feature (identifying 86% of affected horses). So why test horses further? To evaluate their response to treatment!"

Treating PPID

"Many cases do fine with management changes alone," said Schott. "This might include body clipping, regular hoof care, nutrition changes (such as reducing sugars and other rich carbohydrates), and good dental care to ensure proper eating for these older horses.

"Whether a horse needs medication and when that should be started is decided on an individual basis," he added. "When a horse is put on medications, I recommend twice-annual reassessment--clinical examination and glucose/endocrine (hormone) testing. If needed, we adjust medication dosing, then retest the horse in 30-60 days to make sure his (hormone) responses are in the appropriate range."

There's also the issue of the horse that is a possible PPID case, but it's between August and November, so testing is of little value (see take-home message #2). In these cases, "if the owner can afford it, we might treat the horse for a few months just in case, then try to take him off medications and test to see if it's truly warranted," Schott commented.

For confirmed cases, "Is continuous treatment required?" he asked the audience. "We don't really know. Epidemiological studies are hard enough, let alone following horses for 10 years (for the research needed to answer this question)."

Medication options for PPID include pergolide, cyproheptadine, trilostane, and chasteberry extract. One disadvantage is that no treatment is currently FDA-approved for PPID in horses.

Pergolide Schott described several studies that found this once daily medication to be a superior treatment in terms of improved hormone test results and owner assessment of improvement, although the latter might have also been due to improved management.

Disadvantages are that it's expensive (there's a cheaper compounded product available, but you have quality and liability concerns), it causes transient inappetence in some (less than 10% of horses), and it causes lethargy (depression) in rare cases, he said.

Cyproheptadine "This medication used to be less expensive than pergolide; now it's more expensive," Schott commented. Some have suggested that it might act synergistically with pergolide, but he said there were no studies proving this.

Disadvantages include limited efficacy, no pharmacological data, increasing price, and compounded product quality/liability concerns.

Trilostane This targets the adrenal gland to decrease cortisol production, so it could be used with pergolide, Schott commented. "It was shown to be effective in reversing clinical signs in one study in the United Kingdom," he added. "But adrenal cortex hyperplasia (overgrowth and overactivity) is not very common, so trilostane doesn't make sense as a front-line treatment (it doesn't address the pituitary gland dysfunction).

"Also, it's not approved for use in horses, not available in the United States, and pricey," he added.

Chasteberry extract (Vitex agnus castus) Schott reported that in one field study of this product, all owners reported improved demeanor, 22 of 120 horses had improved shedding, and no horses showed changes in hormone levels. In contrast, another study presented at the 2002 AAEP convention found that 13/14 horses deteriorated on the same product.

"Take-home message #4: Spend money on better management rather than questionable products," recommended Schott.

Understanding Pituitary Pars Intermedia Dysfunction (a.k.a. Cushing's Disease)

Pituitary pars intermedia dysfunction--PPID, or Cushing's disease--is the most common disease of horses and ponies 15 years of age or older. Although it's not fully understood yet, researchers are learning more about how to treat and prevent it. Dianne McFarlane, DVM, PhD, Dipl. ACVIM, assistant professor of physiological sciences at Oklahoma State University's Center for Veterinary Health Sciences, discussed normal and abnormal function of the pituitary pars intermedia lobe of the pituitary gland.

"The horse has three distinct lobes of his pituitary gland--the pars distalis, pars intermedia, and pars nervosa," she began. "Each produces different hormones."

The pars intermedia produces a protein called pro-opiomelanocortin POMC) that is converted into adrenocorticotropin (ACTH). This, in turn, is processed into several different hormones:

  • Alpha-melanocyte stimulating hormone (alpha-MSH), a potent anti-inflammatory hormone that plays a role in skin coloring, appetite/satiety balance, and fat metabolism.
  • Beta-endorphin, an endogenous (originating within the body) opioid that provides analgesia and behavioral modification and suppresses immune responsiveness and vascular tone (the degree of blood vessel constriction).
  • Corticotrophin-like intermediate lobe peptide (CLIP), which stimulates insulin release.

Seasonality of Hormones

Season has been recently found to play a big role in secretion of some pars intermedia hormones in horses; this was already known in many other species (humans, hamsters, sheep, and weasels). Alpha-MSH levels are highest in the fall, coinciding with peak body weight, appetite, and body condition in sheep.

This seasonal increase might occur in horses and ponies as well, "to metabolically prepare them for a decrease in accessible food observed in the wild in winter," explained McFarlane. "If so, dysregulation of this pathway might be associated with abnormalities in body weight and fat storage." This might also explain the heavy haircoat of horses with PPID--it's literally a winter coat gone wild.

"Ponies show a much greater response to seasonal hormone changes than horses," she added.

Why is seasonality relevant? Given the increased activity of pars intermedia hormones in the fall, you're more likely to see clinical signs, false positive tests, and PPID-associated laminitis in fall, said McFarlane. This might have implications for treatment as well.

"It's possible that we might be able to treat affected horses (medically) in summer and fall when their hormones are highest, and wean them off medications in winter and spring," she theorized. "This is untested, but it's something to think about for mild cases."

What Causes PPID?

While several mechanisms for PPID have been proposed, McFarlane suggested that it is a neurodegenerative disease. This seems to be supported by the fact that her research has found almost no dopaminergic (dopamine-producing) neurons in the pars intermedia of affected horses, while there are quite a few in young horses or unaffected horses of similar age.

The lack of dopamine is critical, as she noted that the activity of the pars intermedia is normally inhibited (controlled) by dopamine. Without dopamine, the pars intermedia produces much more hormone than it should, causing the clinical signs of PPID.

Similar activity occurs in other species when dopamine is experimentally inhibited, she reported. This explains why the medication pergolide helps so many horses with PPID--it replaces dopamine activity and thus inhibits pars intermedia hormones.

It also explains why another popular treatment--trilostane--doesn't always work as well. McFarlane explained that trilostane acts on the adrenal gland to control secretion of cortisol hormone--"stress hormone." This helps control biochemical stress, but it doesn't act on the originating problem in the pars intermedia.

"I'm hesitant to recommend trilostane partially because it is only available compounded, and because it doesn't act against the inciting factor," she noted. "Pergolide treats in three ways: It protects neurons, adds dopamine, and has antioxidant activity."

Why would a horse's dopaminergic neurons degenerate? McFarlane speculated that oxidative stress, which is more prevalent in PPID horses, and misfolding of a protein called alpha-synuclein, a nerve terminal protein, might play large roles. Misfolding (improperly developing into a form other than its characteristic functional shape) of this protein can be caused by oxidative stress as well. An interesting side note is that this pathway of disease is the same as that proposed for Parkinson's disease in humans, and many biochemical features of Parkinson's closely resemble features of PPID in horses.

"Dopaminergic neurons are particularly vulnerable to oxidative damage, because dopamine metabolism itself produces free radicals (chemically active atoms or molecular fragments that are missing electrons and damage large molecules within cells while attempting to achieve a more stable configuration)," she commented. Other contributing factors might include inflammation and mitochondrial dysfunction (altered activity in the parts of cells that produce energy for carrying out the cell's functions).

PPID Prevention

"I think obesity drives chronic stress, which is a risk factor for neurodegeneration," opined McFarlane. "If we're going to prevent disease, controlling obesity will be very important. Also measure selenium (an antioxidant mineral that horses need in small quantities) and address that if needed, and keep in mind that antioxidant therapy might slow progression of the disease.

"Mitochondrial dysfunction is known to be a contributing factor to Parkinson's disease, and agricultural chemical usage contributes to Parkinson's in humans--these chemicals might well affect horses too," she suggested. "Also, ponies and Morgans seem to be more susceptible to the disease. What that genetic factor is, we'll understand better with more research. Understanding the mechanisms of disease is essential to knowing how to prevent this disease in these animals."

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