Literature Review: The Relationship of Weight Loss on Diet & Exercise Interventions

Literature Review: The Relationship of Weight Loss on Diet & Exercise Interventions

By: Libby Quincey 

I. INTRODUCTION
The plague of obesity is sweeping the nation and about one-third of the United States population between the ages of 20 and 74 are classified as obese (Volpe, Kobusingye, Bailur, & Stanek, 2008).  Today, more than ever, new restrictive diets and quick fixes are heavily marketed with promises to improve body image and lose weight.  Commonly with these low calorie diets, the quick weight loss is linked to muscle wasting, weight regain, and detrimental changes of metabolic pathways, that function to maintain homeostasis by conserving energy and providing cellular feedback (Lorkowski, 2011; Andersson, Karlstrom, Freden, Petersson, Ohrvall, & Zethelius, 2008).  A weight loss program that combines physical activity and moderate caloric reductions, with the proper ratio of protein and carbohydrates: promotes fat loss, maintains and elicits gains in lean body mass, and enhances metabolic health (Layman, et al., 2003).

The purpose of this review is to investigate the relationship between weight loss on diet, exercise, or the combination of diet and exercise interventions.  Section II, investigates obesity and the complications with lipotoxicity and insulin signaling.  Section III, restrictive dieting, the most common weight loss treatment for obesity, is investigated and linked to detrimental reductions in lean body mass.  Exercise, another weight loss method, is investigated and associated with lean body mass and glucose uptake improvements in type 2 diabetes, but only modest fat loss changes.  Section IV, research of diet and exercise interventions has been complied and compared among diverse populations.  In section V, research of diets that vary in protein and carbohydrate ratios and exercise are investigated.  Finally, in section VI, the weight loss interventions are compiled and the most effective treatment for obesity is summarized.

II. POSTIVE CALORIC BALANCE: OBESITY & LIPOTOXICITY  
Obesity, the disorder of energy balances, occurs when energy intake exceeds energy expenditure (Kraemer, et al., 1999).  Positive caloric balance is due to a continuous calorically dense intake, usually high in carbohydrates and dietary fats, followed by physical inactivity that ultimately manifests into metabolic disruptions and lipid overload (Chakravarthy & Booth, 2004).  The accumulation of body fat is associated with the onset of various health risks that compromise the vitality of tissues and organs, including lipotoxicity and type 2 diabetes (Layman, et al., 2003).  Today, obesity is a public health concern in the United States and its treatment should incorporate the two precursors of obesity, energy intake and energy expenditure (Ross, et al., 2000).

After a meal, dietary fat is broken down and absorbed through the intestine and enters circulation as chylomicrons. Insulin stimulates the enzyme lipoprotein lipase (LPL), which interacts with the chylomicrons at the endothelial cell surface to hydrolyze the triglycerides found in the chylomicrons, releasing free fatty acids. The free fatty acids are taken up by the adipose tissue with the help of diacylglycerol acyltransferase (DGAT), re-esterified into triglycerides to be stored in the form of lipid droplets (Cianflone, 1997; Cianflone, Maslowska & Sniderman, 1999).  Free fatty acids (FFA) are imported into the cell by protein and non-protein mediated mechanisms, either to supplement energy demand or when extracellular FFA concentrations are high (Schaffer, 2003).

High plasma levels of free fatty acids (FFA), elevated triglyceride levels, and decreased FA oxidation, may lead to FFA accumulation in nonadipose tissues (Herpen & Schrauwen-Hinderling, 2007; Unger, 2003).  Fatty acids accumulate in tissues such as the liver, skeletal muscles, and pancreatic βBeta-cells due to an overload at adipocytes (St-Pierre, et al., 2008).  Unlike adipocytes, these vital organs have a limited fat storage capacity and when this capacity is surpassed then cellular dysfunction occurs.  Receptors and cytokines throughout the body are disrupted and the lipid overload manifests into a syndrome known as lipotoxicity (Schaffer, 2003).  When excess fats are moved to the pancreas thenpancreatic Betaβ-cells in the pancreas, apoptosis occurs, and thenwhich causes decreased insulin productions.  As a result, when insulin does not properly stimulate the enzyme lipoprotein lipase (LPL), that hydrolyzes triglycerides and promotes adipocyte storage, fat storage occurs within the skeletal muscle and impairs the insulin sensitivity of this tissue.  High levels of FFA and glucose remain in the blood stream and could lead to insulin resistance and ultimately progress to type 2 diabetes (Li & Hui, 2009; Schaffer, 2003).

Figure 1: These regulatory roles in glucose and lipid metabolism with leptin, adiponectin, and ASP are disrupted (Ben-Ezra, 2006).

The metabolism of dietary fats and carbohydrates are intertwined and the metabolic abnormalities associated with these substrates are interconnected as well (Hue & Taegtmeyer, 2009).  Hence, when energy balance is disrupted, this may manifest into an array of health complications that feed off of one another, like insulin resistance, type 2 diabetes, and lipotoxicity.  These metabolic disorders compromise vital tissues and organs and cause a cascade of problems to occur; altering regulatory hormone production as well as energy storage.  Lipotoxicity alters hormone production at the adipocytes, such as leptin, adiponectin, and acylation stimulating protein (ASP) (Havel, 2002).  As a result, their regulatory roles, which are depicted in Figure 1, are inhibited (Li & Hui, 2009; Ben-Ezra, 2006).  Chronically elevated leptin and ASP and supressedsuppressed levels of adiponectin are associated with metabolic disruptions in glucose and lipid roles, which lead to diabetes and plasma lipid abnormalities (Havel, 2002; Cianflone et al., Xia, & Chen, 2003).  According to Figure 2, when leptin is not performing its regulatory role, the Jak/STAT pathway is not activated.  High levels of acetyl CoA carboxyl (ACC) generate malonyl CoA, the lipogenic precursor and inhibitor of fatty acid oxidation.  More fatty acids and triglycerides are synthesized and less oxidation happens.  This causes the content of triglyceride and fatty acyl CoA to increase in lean tissues (Unger, 2003).  Abnormal liporegulation leads to the accumulation of fat in the body that impairs the insulin-sensitivity of peripheral tissues (Stannard & Johnson, 2003).

Figure 2: Abnormal liporegulation due to leptin action (Unger, 2003).  The utilization and import of FFA are disrupted.

Impaired hormonal production and energy storage disrupts cellular functions (Unger & Orci, 2001).  At the skeletal muscle level, high amounts of FFA lead to intramyocellular triglyceride content (IMTG), which decreases mitochondrial activity and inhibits fatty acid B-oxidation.  The accumulation of IMTG may interfere with the insulin-signaling pathway by increasing levels of long chain acetyl-CoA, ceramide, or diacylgerol.  Due to this relationship, insulin resistance and the accumulation of intramyocellular triglyceride content (IMTG) in the body directly impairs insulin sensitivity in the pancreas, skeletal muscles, and liver (Stannard & Johnson, 2003; Schaffer, 2003).    As depicted in Figure 3, intracellular FFA activates the serine/theronine kinase cascade that inhibits the insulin receptor substrate-1 tyrosine phosphorylation.  The insulin receptor substrate-1 is not phosphorylated so insulin is unable to bind it’sits receptor.  Phosphatidylinositol 3-kinase (PI3K) and the insulin-signaling pathway isare inhibited.  This leads to the inability to promote the translocation of the GLUT-4 glucose transporter to the plasma membrane and glucose is unable to enter the cell (Saltiel & Kahn, 2001; Schaffer, 2003).  Extracellular glucose levels remain elevated and glucose, the source of the glycerol molecule that is the backbone of a triglyceride molecule, is not properly stored (Maslowska et al., 1997)  These) These changes in signaling pathways are associated with accumulation of intracellular fatty acyl-CoA and diacylglycerol (DAG), rather than triglyceride and ceramide (Schaffer, 2003).    

Figure 3: The insulin-signaling pathway is inhibited due to lipid accumulation in the skeletal muscle (BenEzra, 2012).

The health complications of obesity are vast and impair the body’s mechanism which that regulates carbohydrate and fat metabolism (Hue & Taegtmeyer, 2009).  Overall, abnormal regulatory carbohydrate and lipid metabolism pathways cause: decreased glucose uptake, impaired hormonal response, elevated plasma free fatty acid (FFA) levels, hyperglycemia, and an inflammatory response (Unger, 2003).  The lipid-induced dysfunction in lean tissue caused by lipotoxicity is commonly associated with obesity, insulin resistance, and type 2 diabetes.  There is a direct association between fat accumulation and impaired carbohydrate metabolism and the factors that contribute to these health complications need to be addressed (Havel, 2002).  Today, restrictive dieting remains the most common method of obesity reduction (Cogan, 1999; Ross, et al., 2000).  This restrictive dieting strategy does not incorporate energy expenditure (exercise) one of the major causes of obesity and weight loss is not maintained over long term (Wycherley et al., 2010).  In fact, physical activity has shown to improve glucose uptake and improve fat utilization, the two mechanisms linked to these obesity-related diseases, lipotoxicity and type 2 diabetes (Sriwijikamol, et al., 2007; Jessen & Goodyear, 2005).  However, the combination of inactivity and restrictive food intake remains the popular solution for weight loss.  According to research, the combination of inactivity and restrictive dieting has been shown to exacerbate the catabolic state and enhance detrimental reduction in lean body mass (Biolo, et al., 2007).  Lean body mass may be conserved by exercise, but research has shown exercise alone does not elicit great gains in fat reduction (Holten, et al., 2004; Ross, et al., 2000).  

III. RESTRICTIVE DIET or EXERCISE TREATMENT
Obesity is associated with an array of life threatening complications and a weight loss treatment is essential, but the solution is elusive (Ross, et al., 2000).  Famine, due to food scarcity, has been documented as a phase in the cycle of life during prehistoric times.  This phase was followed by the cycle of feast, physical activity, and rest (Chakravarthy & Booth, 2004).  Today, in a cycle of “food abundance,” food scarcity elicited by restrictive dieting seems like the plausible solution.  However, research has shown that restrictive dieting is not the solution and has shown to have a 95% failure rating for long-term weight loss (Cogan, 1999).  It enhances the catabolic state, neglects energy expenditure, and compromises skeletal muscles that are essential for glucose uptake and hormonal regulation (Biolo, et al., 2007).  In contrast, energy expenditure may promote improvements in glucose uptake and lean body mass maintenance, but produces only modest fat loss reductions (Holten, Zacho, Gaster, Juel, Wojtaszewski, & Dela, 2004; Ross, et al., 2000).  
 
In the 1950s, Dr. Albert T. Simeons claimed that a very low calorie diet (~500 kcal/day) supplemented with the human chorionic gonadotropin (HCG) was a successful treatment for obesity and weight loss (Robb-Nicholson, 2010). The hormone, HCG, is present in pregnant women’s urine and stimulates the corpus luteum to produce estrogen and progesterone (Oz & Roizen, 2011; McCary, 2011).  Dr. Simeons reported that 500 patients lost between 20-30 pounds in 40 days and reported to release stored fat for energy usage and reduce hunger sensations (Robb-Nicholson, 2010).  In contrast, according to a meta-analysis of 24 studies by Lijesen et al. (1995), no evidence supports these HCG weight loss “claims.”  Documented complications include blood clots, headaches, restlessness, depression, and dizziness (Lijesen, Theeuwen, Assendelft, & Van Der Wal, 1995; Hellmich, 2011).  Even today, these “claims” of targeted weight loss and reduced hunger with the HCG diet are not scientifically proven, but this type of inadequate nutrition provided by very low calorie diets can lead to metabolic disruptions and detrimental fat free mass reductions (Lijesen et al., 1995; McCary, 2011).

Dietary nutrients are oxidized, broken down, or serve as intermediates in the synthesis of other biological molecules.  Metabolic pathways are tightly organized and coordinated into a series of consecutive enzymatic reactions (Lorkowski, 2011).  These intertwined, anabolic and catabolic pathways, perform regulatory roles that utilize specific substrates to release hormones and regulate metabolism.  During catabolic periods caused by very low calorie diets, molecules stored in cells are broken down and converted into building blocks needed for energy in order to maintain energy and blood glucose levels (Chakravarthy & Booth, 2004; Lorkowski, 2011).  After an overnight fast, mainly glycogen stores in the liver are utilized, but within 48 hours these stores are depleted and moderate decreases in muscle glycogen occur (Rubio-Aliaga, et al., 2011).

It can be suggested that prolonged fasting produces detrimental reduction in muscle glycogen and proteins throughout the body.  This negative energy imbalance is the opposite of positive caloric balance, associated with obesity.  The body is depriving itself from energy intake and the regulatory roles and vital organs are compromised similar to the other imbalance (Manninen, 2004; Rubio-Aliaga, et al., 2011).  The combination of restrictive dieting and inactivity may lead to decreased turnover of skeletal muscle proteins and impaired dietary amino acid utilization, which may lead to muscle deregulation and atrophy (Biolo, et al., 2007).  In a study by Biolo et al. (2007), the effect of inactivity for 14 days, and calorie restriction on lean body mass and protein kinetic regulation was investigated.  The study protocol was divided into four phases; the first and second phase evaluated the eucaloric diets on either bed rest or ambulatory conditions.  In the third and fourth phase, hypocaloric diets were compared on either bed rest or ambulatory conditions.   After each phase, the rate of net leucine disposition of body protein was calculated from the difference between nonoxidative Rd (synthesis) and Ra (proteolysis).  Leucine is an amino acid that directly stimulates protein synthesis (Layman & Baum, 2004).  The hypocaloric diet reduced fat intake to a minimum of 60 g/day and measurements were recorded in 9 healthy volunteers.      

In Figure 4, the net leucine was significantly lower in the bed rest conditions (p <0.01).  The combination of bed rest and caloric restrictions led to higher rates of leucine oxidation (p= 0.04), a marker of net protein catabolism, and to less nonoxidative leucine Rd, a marker of protein synthesis in the postabsorptive state.  This suggests that calorie restriction enhanced the catabolic response to inactivity by enhancing greater protein catabolism in the postabsorptive state.

Figure 4: The net protein deposition calculated in the four phases of the study: the eucaloric diet on bed rest (BE), eucaloric diet on ambulatory condition (AE), hypocaloric diet on bed rest (BH), and hypocaloric diet on ambulatory conditions (BH).

 Amino acids are the fuel for the liver and serve as substrate for hepatic gluconeogenesis (Rubio-Aliaga, et al., 2011).  Leucine provides fuel for skeletal muscle and serves as a modulation of PI3K signaling cascade for insulin.  Leucine’s regulatory roles are dependent on intracellular concentrations and decrease in leucine limits the oxidation use of glucose by the muscle and inhibits skeletal muscle mass maintenance.   Leucine bypasses the liver and is transaminated in the muscle, brain, and kidney and regulate metabolism in these organs.  When the high demand for substrates for gluconeogenesis is not met by glycerol, then amino acids derived from the muscle are used (Layman & Baum, 2004).  As a result, high levels of amino acids in the plasma, indicates that proteolysis, the breakdown of proteins, has occurred (Rubio-Aliaga, et al., 2011).  In this study, caloric restriction increased concentrations of the following amino acids in the plasma: serine, glycine, threonine, arginine, methionine, valine, isoleucine, and leucine.  The increments of amino acid plasma concentrations did not significantly differ between bed and ambulatory conditions during the eucaloric or hypocaloric diets.  However, the findings suggest that proteolysis occurred at a higher rate in calorically restricted bedridden participants.

Table 1: The hypocaloric and bed rest had a negative change in LBM that was significantly different than hypocaloric ambulatory and eucaloric bed rest.

	Eucaloric & Ambulatory	Eucaloric & Bed Rest	Hypocaloric & Ambulatory	Hypocaloric & Bed Rest
Weight Loss	0.0 + 0.3	-0.6 + 0.2	-1.4 + 0.3*	-2.1 + 0.2*
Lean Body Mass	-0.1 + 0.1	-0.3 + 0.2	-0.3 + 0.3	-1.1 + 0.1*
Fat Mass	0.1 + 0.3	-0.3 + 0.2	-1.0 + 0.3	-1.0 + 0.3

In addition, the hypocaloric and bed rest group lost about 2% of their lean body mass.  This reduction in lean body mass paralleled the reductions of fat mass.  In comparison to the other groups, the hypocaloric and bed rest group showed significantly higher lean body weight reductions (p< 0.01).  According to Table 1, both caloric restriction groups showed a significant decrease in weight loss from baseline measurements.  In both ambulatory and best rest conditions, there was approximately an 8% decrease in fat mass.  It was suggested that the loss of lean body mass in bedridden participants was accelerated by inadequate caloric consumption.  Also, during a fasted state due to a very low calorie diet, stress mediators, like cytokines and cortisol, may amplify the catabolic reaction of lean body mass.
During negative caloric balance from restrictive dieting, low plasma insulin levels and increases of glucagon and catecholamines serve as feedback mechanisms for the body, shown in Figure 5 (Rubio-Aliaga, et al., 2011).  The catabolic hormone, cortisol, which is produced from the adrenal gland, has the ability to increase blood glucose levels and decrease insulin sensitivity (Unger, 2003).  This survival mechanism of eliciting insulin resistance helps to maintain blood glucose levels for brain function (Chakravarthy & Booth, 2004).  However, chronically elevated catabolic hormones, like cortisol, have been associated with major health-complications; such as: detrimental reductions in muscle growth due to inhibited anabolic hormone production, reduced strength, and impaired bodily systems, such as the immune response (Biolo, et al., 2007; Rubio-Aliaga, et al., 2011).  Restrictive dieting is associated with reproductive and cardiovascular problems, amenorrhea, hypothermia, renal complications, blood dysfunction, and osteoporosis (Cogan, 1999).

Figure 5: Negative protein balance is the catalytic state produced during fasting (University of Oklahoma, 2010).

As a result, hypocaloric dieting and inactivity as a weight loss treatment may lead to metabolic and health complications and detrimental reduction in muscle mass (Biolo, et al., 2007).  In contrast, another weight loss treatment of solely exercise, addresses energy expenditure in the obesity equation (Ross, et al., 2000).  Exercise has been shown to preserve lean body mass, enhance skeletal muscle mass, and promote glucose uptake in type 2 diabetics.  These gains in skeletal muscle provide stability, mobility, strength, and improved regulation of carbohydrates, lipids, and proteins (Schardt, 2011).  However, according to research increasing energy expenditure in the absence of energy intake will only promote modest weight loss (Holten et al., 2004; Ross, et al., 2000).

Single exercise sessions are associated with significant improvements in insulin-stimulated glucose uptake (Ross, et al., 2000; Musi et al., 2001).  The skeletal muscle is responsible mainly for the peripheral disposal of glucose during an exercise bout and improvements of carbohydrate metabolism have been linked to resistance and aerobic training (Musi et al., 2001).  In a study of participants (n=64), between the ages of 39-70, with type 2 diabetes, 7 resistance-training exercises were performed three times a week.  After 22 weeks, hemoglobin, A1c, which reflects long-term blood glucose levels, was significantly lower than the A1c levels reflected in the control (n=63) (Sigal, et al., 2007). This study suggests that impaired glucose tolerance in type 2 diabetics can be improved by strength training. According to a study by (Sriwijikamol, et al., (2007),  aerobic exercise for 40 minutes at moderate intensity, decreased mean plasma glucose levels in the type 2 diabetic subjects by 1.3 mmol/l.  This study suggested that improved glucose uptake is stimulated by moderate aerobic exercise in subjects with type 2 diabetes. Residual effects of energy expenditure also showed improved insulin sensitivity and modest glucose uptake, even 24 hours after exercise (Musi et al., 2001).  It is suggested that the AMPK stimulation can help to correct insulin resistance and high-to-moderate intensity exercise has shown significant improvements in glucose uptake.

After exercise training, increases insulin action on skeletal muscle is associated with increased GLUT-4 protein that transports glucose into the cell and enzyme responses involved in metabolism (Holloszy, 2005).  Muscle contraction causes the stimulation of AMPK and bypasses the insulin-signaling pathway to promote the translocation of GLUT-4 to the cell membrane and T-tubules and it bypassing the insulin-signaling pathway, as shown in Figure 6.  Skeletal muscle contraction activates a number of signaling proteins, AMP-activated protein kinase, calcium activated kinases, nitric oxide, bradykinin, and AS160 (Jessen & Goodyear, 2005).  During exercise, there are two pathways that stimulate AMPK.  In the first pathway, skeletal muscle contraction is activated by the depolarization of T-tubules and membrane.  This stimulates the secretion of Ca2+ from the SR and activates CAMKII.  The other pathway that activates AMPK is initiated when ratios of energy (ATP) and creatine phosphate are low (Holloszy, 2005).  AMPK stimulates TBC1D1 protein and AS160, the link between AMPK and insulin-signaling pathway.  It addition, AMPK conserves energy by turning on ATP-generation pathways.  The TBC1D1 protein ultimately activates the GLUT-4 transporter protein.  However, the signaling mechanism that controls the glucose transporter protein is unknown.  The activation of AMPK due to exercise contributes to improvements of lipid and glucose metabolism (Musi et al., 2001; Sriwijikamol, et al., 2007).

Figure 6: This is an example of how muscle contraction bypasses the insulin-signaling pathway to promote GLUT-4 transporter protein (BenEzra, 2012).



During exercise, depletion of muscle glycogen is followed by enhanced glycogen synthesis (Holten et al., 2004).  Similarly, during fasting states, depletion of muscle glycogen stores occurs and is eliminated within 48 hours  (Rubio-Aliaga, et al., 2011).  Following prolonged fasting, the body responds in a survival type fashion and immediate energy storage occurs to restore intramyocellular triglyceride (IMTG) and regain weight loss (Chakravarthy & Booth, 2004).  As a result, the anabolic and catabolic pathways are deregulated due to the energy imbalances elicited from restrictive dieting (Manninen, 2004; Rubio-Aliaga, et al., 2011).  Energy expenditure helps to control and regulate the metabolism and improves glycemic control.  These are components associated with obesity, insulin resistance, type 2 diabetes, and lipotoxicity (Holten et al., 2004; Layman & Baum, 2004).    
     
In order to design an effective weight loss treatment, both energy intake and energy expenditure needs to be addressed and balanced (Ross, et al., 2000).  Negative energy balance from restrictive dieting is associated with catabolic health-complications and detrimental reductions in muscle mass (Biolo, et al., 2007).  Today, popular diets like, the HCG diet, market weight loss “claims” that are ineffective and produce unfavorable health complications or “side effects” (Lijesen et al., 1995)  Another weight loss treatment of solely exercise has been associated with improved glucose metabolism but has been ineffective to elicit fat loss (Ross, et al., 2000).  In 13 randomized studies, the relationship of exercise only in overweight men and women reduced total and abdominal fat only modestly, by approximately 2kg or 2% (Holten, et al., 2004).  However, the combination of mild caloric restrictions and physical activity have been associated with significant fat loss, maintenance of lean body mass, and enhanced metabolic health (Layman, et al., 2003).

IV. DIET & EXERCISE INTERVENTIONS

Today, the market is flooded with inaccurate information about nutrition, dieting, and weight loss.  In order to promote metabolic homeostasis, it is imperative to balance dietary intake and exercise.  The weight loss treatment focus should be improving overall health, improving lean body mass, and decreasing the risk of metabolic disorders (Cogan, 1999).  The problem with accelerated weight loss typically marketed today is that it alters the energy balance within the body and weight loss is linked to reductions in fat free mass (Layman & Baum, 2004).  In order to adequately address obesity and the health complications associated with it, the two precursors of energy intake and energy expenditure need to be incorporated in the treatment (Ross, et al., 2000).  

In a randomized study by Ross et al. (2000), fat (total, subcutaneous, and visceral), skeletal muscle mass, cardiovascular fitness, glucose tolerance and insulin sensitivity were compared obese men (n=52).  The participants were assigned to one of the following groups: diet only, exercise and diet, exercise only, and control.  The composition of dietary intake was:  55-60% carbohydrate, 15-20% protein, and 20-25% fat.  The diet group was instructed to reduce their intake by 700 kcal/day.  The exercise groups performed daily exercise on a treadmill for 12 weeks at an intensity less than 70% of their VO2peak to expend 700 kcal.  After an overnight fat, a 75-g oral glucose tolerance test was administered and on another occasion insulin sensitivity was measured by estimating glucose disposal rate (GDR) with the euglycemic hyperinsulinemic clamp (EHC) technique.

After 3 months, both exercise groups improved peak VO2 by about 16% compared to the controls (p <0.01).  When comparing the two diet interventions to the control, both produced significant weight loss and significant improved GDR.  This supports the association between glucose disposal rate and adipose tissue.  Increase visceral and body fat is directly related to increase glucose tolerance and insulin resistance at peripheral tissues (Chakravarthy & Booth, 2004).  Therefore, the decrease in fat, especially visceral fat, was more sensitive to lipolytic stimulation and the anabolic hormone insulin.  The diet group showed an average total abdominal fat reduction of about 1.5 kg and the exercise and diet combination showed a slightly higher reduction of 1.9 kg.  In addition, the exercise and diet group showed a higher average total fat reduction of 1.3 kg (p=0.03) than the diet only group.  The total fat reduction in participants assigned to the exercise only group was similar to the control and this suggests the exercise only group resulted in only modest weight loss, as previously found in research (Holten et al., 2004).  Skeletal muscle mass in the diet-induced weight loss group decreased, but remained unchanged in both the exercise groups.   Overall, the combination of exercise and diet avoided muscle mass reduction, and improved metabolic health and was the optimal weight loss strategy in this study (Ross, et al., 2000).

According to another study of similar findings, the participants were randomly assigned to the following groups: diet only, exercise only, and the combination of exercise and diet (Volpe, et al., 2008).  The study consisted of men and women (n=90) with a body mass index between 27 and 35 kg/m2.  Body weight and body composition were measured every 3 months, and leptin levels evaluated at 6 months.  The exercise groups exercised in a class on a Nordictrack for 30 minutes, 3-4 days/week, and then after 3 months increased frequency to 5 days/week.  At 7 to 12 months, the Nordictrack and exercise regimen was sent home with the exercise participants and they were reminded to complete their exercises.  The diet group was instructed to keep a 3-day diet recall and attended nutrition classes for the first 6 months.  Then the participants dieted without the supervision of dieticians or the support of the nutrition classes for the remainder of the study.      

It was found that at 6 and 9 months, women had significantly lower body weight than at baseline in the diet and exercise group, as shown in Figure 7.  At 9 months, in comparison to other interventions, the men in the diet and exercise group showed significantly higher weight loss, as depicted in Figure 8.  However, at 12 months, there showed no significant difference between the groups due to lack of adherence to the self-monitored diet and exercise program (Volpe et al., 2008).

Figure 7: The relationship of body weight loss among women.

Figure 8: The relationship of body weight loss among men.

At 6 months, leptin levels decreased in women among the diet only group (p= 0.05) and diet and exercise group (p= 0.0003).  Leptin levels decreased in men among the exercise only group (p= 0.038) at 6 months (Volpe et al., 2008).  As previously noted, the adipocyte produced hormone, leptin signals the brain and muscle to regulate the metabolism.  These reductions in leptin may be associated with fat loss; the body is more leptin sensitive with lower levels (Havel, 2002).  As a result, leptin will perform its regulatory roles in fat oxidation and triglyceride storage that were previously inhibited in states of metabolic abnormalities.  As depicted in Figure 7, leptin will bind to its receptor, OB-Rb to initiate the phosphorylation of Janus kinase (Jak)/STAT and STAT-3 enters the nucleus.  This increases PGC- 1 and the enzymes of fatty acid oxidation, CPT-1 and acyl-CoA oxidase (ACO).  AMPK phosphorylated and blocks malonyl CoA, the substrate for fatty acid synthesis.  CPT-1 transports FA across the membrane and mitochondrial oxidation of fatty acids.  Leptin is able to maintain fatty acid oxidation at an appropriate level and prevent overaccumulation of fat (Unger, 2003).  This study suggests that the combination of diet and exercise can decrease body weight and lower leptin levels, which are associated with improved fat regulation and the prevention of lipotoxicity.  However, the weight loss program needs to be maintained in order to prevent weight regain (Volpe et al., 2008).  

Figure 9: Normal liporegulation and the actions of leptin (Unger 2003).

In a study by Ballor et al. (1988), the effects of diet and an 8-week resistance-training program on lean body mass among obese women (n= 40) was evaluated.  The diet was 50% carbohydrates, 27% protein, 23% fat, and included protein supplements.  The protein supplement was taken with 8 fl oz of milk and supplied about 25 g/day of protein to ensure that protein intake was greater than 1.0 g/kg.  The weight training consisted of 8 exercise, 3 day/week, and 10 repetitions were performed in the first two sets and then as many repetitions as possible in the third set.  The program performed was a muscle overload resistance training design.

According to the findings shown in Table 2, the combination of weight training and diet elicited the highest fat loss.  The resistance exercise groups showed significant increased in lean body weight compared to the diet only group.  The diet and exercise group maintained and promoted lean body mass and the protein supplementation helped to support muscle growth.  The control and diet only participants lost lean body mass.  Adequate protein intake may help maintain lean body mass and increase calories expended as fat and decrease the need to deaminate amino acids to supply energy, as previously shown in Biolo et al. (2007) (Layman & Baum, 2004).  The resistance training showed improved muscle strength and improved body composition by promoting gains in lean body mass and reducing fat mass.  Resistance training has shown improvements in glucose uptake and improved metabolism of intertwined carbohydrate and lipid pathways (Sigal, et al., 2007).  This study suggests that resistance training maintains lean body mass during mild dietary restrictions and this was the most effective treatment to promote fat loss.


Table 2

	Control (C)	Diet (DO)	Weight Training (EO)	Weight Training & Diet (DPE)
Weight (kg)	-0.38	-4.47	0.45	-3.89
Fat (kg)	-0.07	-3.56	-0.62	-4.32
Lean mass (kg)	-0.31	-0.92	1.07	0.43

 In a study by Kraemer (1999), the purpose was to determine if dieting and resistance training may prevent reductions in fat free mass and improve muscular strength, body composition, and metabolic rate.  The male participants were assigned to one of the following groups: control (C), diet (D), diet and endurance training (DE), and diet, endurance, and resistance training (DES).  The diet consisted of pre-packaged food with an adequate protein intake (greater than 1.1g/kg), vitamins, minerals, and high fiber.  The exercise consisted of the following endurance training activities (treadmill walking and jogging, stationary cycle, and stationary stair climber) at 70-80% of their target heart rate and increased intensity and duration overtime.  Resistance exercises for each of the major muscle groups were performed and varied from heavy (5-7 RM) and moderate (8-10 RM) loads.
According to the findings, the diet only group showed no beneficial changes in body composition, resting metabolic rate (RMR), and muscular power.  At 12 weeks, DES showed the greatest percent body fat loss at 8.42% compared to D at 3.62% and DE at 4.7%.  In Figure 10, fat free mass was not completely preserved with the heavy resistance, and exercise training but offers advantages to body composition than diet alone.    

Figure 10: The differences in body mass, fat mass, and fat free mass changes in following groups: control (C), diet (D), diet and endurance training (DE), and diet, endurance, and resistance training (DES).

Peak oxygen consumption was significantly elevated in the DE and DES groups, by 24.8% and 15.4% respectively.  The diet only group demonstrated a significant decline in peak and mean output at week 6 and remained lower at week 12 in the Wingate anaerobic cycle test.  After week 12, resting metabolic rate was lower in D by 80 kcal/day and DES by 136 kcal/day and significantly different from baseline in DE by 122 kcal/day. Resting metabolic rate is improved with greater muscle mass content and there is a direct association between muscle mass content and caloric expenditure (Schardt, 2011).  There were no cortisol changes for any group.  Even though, usually heavy resistance training has been shown to decrease resting cortisol levels in men and increase testosterone levels.  Discrepancies in the study may be due to the differing training intensities and incorporating periodization in the training program.  However, all three-intervention groups showed significant and similar reduction in overall body mass, but the body composition of weight loss varied.  The diet with resistance and endurance training improved peak oxygen consumption, and showed the highest impact on body composition, and maintaining power production capabilities.  This study suggests the combination of aerobic and resistance training with diet will be the most effective treatment for improving overall health and body composition.

According to these studies, the combination of exercise, both aerobic and resistance training, and mild caloric reductions was unanimously the most effective weight loss treatment.  The combination of energy intake and energy expenditure showed improved weight loss, fat loss (visceral and total body), resting metabolic rate, oxygen consumption, and maintenance of skeletal muscle and amino acids.  Leptin levels decreased which promoted fatty acid oxidation and the metabolism of carbohydrates improved with higher rates of glucose disposal (Havel, 2002; Unger, 2003).  In the study by Ballor et al. (1988), protein was investigated to elicit and support anabolic growth during mild caloric restrictions.  This relationship has been shown to be effective and may be an important component to integrate in a weight loss program (Ballor et al., 1988; Layman & Baum, 2004).  The HCG placebo claims of targeted weight loss and reduced hunger sensations are scientifically proven in these studies of exercise and dieting interventions (Lijesen et al., 1995).      

V. PROTEIN & CARBOHYDRATE RATIO
Macronutrients consist of carbohydrate, lipid, and protein nutrients that support structural and functional capacity of the body. (McArdle, Katch, & Katch, 2006)  The body requires macronutrients to maintain health and to stimulate specific hormones and chemicals that are necessary for metabolic regulation and maintaining health.  (Lorkowski, 2011)  The human metabolism is intertwinned and works in a balancing act to control and utilize substrates.  When the body is not properly fueled then it will compromise its own organs and muscle to provide substrate for utilization, shown in Biolo, et al. study (2007).  This has been associated with reductions in lean body mass, disruptions in hormones and cytokines, altered metabolic pathways, and impaired insulin-signaling cascade (Havel, 2002).  In contrast, diets high in fat and carbohydrates contribute to obesity.  Obesity is associated with reduction in B-oxidation, increases triglycerides and fatty acids in the plasma, which leads to nonadipose tissue storage.  This is associated with reductions in satiety, which may be linked to chronically elevated leptin levels and abnormal liporegulation (Unger, 2003; Havel, 2002).  Therefore, the optimal ratio of macronutrients is imperative to ultimately support body composition changes and provide muscle growth due to exercise (Layman & Baum, 2004).  

In a study by Layman et al. (2003), female participants (n=24) between the ages of 45-56 yr old were assigned to two different isoenergetic diets for 10 weeks.  The diets between groups had the same amount of total fat (~50 g/day), calories (1,700 kcal/day), and fiber (~20 g/day).  The two groups were: CHO group with a ratio of 3.5 carbohydrates for every 1 protein (0.8 g/kg), and PRO group with a ratio of 1.4 carbohydrates to every 1 protein (1.6 g/kg).

Figure 11: The differences in the ratio of fat loss to lean loss (g/g) in CHO and PRO group.

According to Figure 11, it was found that CHO group lost about 7 kg body weight, the ratio of fat to lean muscle was 3.8 g/g.  The PRO lost ~ 7.5 kg body weight, the ration of fat to lean muscle was 6.3 g/g.  The loss of lean body mass was greater in the CHO group (1.21 + 0.55 kg) than the PRO group (0.88 + 0.33 kg).  The protein group maintained lean muscle, reported higher satiety levels, and maintained levels of the thyroid hormone, T3 and T2.  At week 2, PRO group had higher concentrations of T3 and had higher T4 concentrations at week 10.  The PRO group showed reduced insulin response in a 2-hour postprandial test meal than the CHO group, 251+ 21 and 384 + 27 pmol/L respectively.

Therefore, this study suggests that an increase proportion of protein to carbohydrate ratio has a positive effect on body composition, hormone leptin, and satiety during weight loss.  Both groups lost body weight, but the protein group was more effective in improving body composition.; the protein promoted muscle synthesis during a catabolic condition (Ballor, et al., 1988; Layman & Baum, 2004).  The protein group reported to have higher satiety, which may be due to the protein, dietary fiber, and fluid intake.  However, it is important to note that leptin is known as the satiety hormone.  Even though, leptin was not measured in this particular study, the fat loss was higher in the protein group and reductions in fat loss is associated with improved leptin sensitivity.  The satiety levels may have been associated with more leptin regulation due to enhanced weight loss in the protein group (Unger, 2003; Havel, 2002).

This study indicated that a higher ratio of protein to carbohydrates resulted in increased rates of lipolysis with higher fat loss; while maintaining thyroid hormones levels.  The thyroid hormone increases metabolism, enhances catecholamine effects, and stimulates growth and development.  This study suggests that more protein intake would decrease muscle loss and maintain muscle mass and protein synthesis during catabolic conditions.  In short, research from various weight loss interventions have shown that incorporating exercise training and proper ratios of macronutrients elicits targeted fat loss and reductions in leptin levels, which suppresses hunger sensations (Layman, et al., 2003; Volpe et al., 2008).  Targeted fat loss and improved satiety levels are two weight loss “claims” of the HCG placebo diet that have never been scientifically proven (Lijesen et al., 1995; Hellmich, 2011).  In contrast, incorporating energy intake and energy expenditure into a weight loss has been documented as the most effective long-term lifestyle intervention technique (Ross, et al., 2000).    

In a study by Wycherley et al. (2010) that lasted 16 weeks, a total of 83 type 2 diabetic participants, both male and female, were recruited by public advertisement (BMI 35.3 + 4.5 kg/m2).  It investigated the effects of body weight, body composition, waist circumference, and other risk markers on diet and exercise.  The participants were randomly assigned to one of the following groups: a carbohydrate diet (control), high protein diet (HP), carbohydrate diet and resistance exercise (CON+RT), or a protein diet and resistance exercise training (HP+RT).  The resistance-training regime was 3 days/week, at 70-85% 1 RM for 8-12 repetitions.  The carbohydrate diet consisted of 53% carbohydrate, 19% protein, and 26% fat of total calories, which reflected the standard dietary recommendations.  The protein diets had 43% carbohydrate, 33% protein, and 22% fat of total calories; designed to achieve a 25% greater intake of protein (1.12 g/kg).

Table 3

	Control	HP	CON+RT	HP+RT
Weight (kg)	-8.6 + 4.6	-9.0 + 4.8	-10.5 + 5.1	-13.8 + 6.0
Fat (kg)	-8.2 + 4.6	-8.9 + 3.9	-11.3 + 4.6	-13.7 + 4.6
Lean mass (kg)	-2.2 + 1.9	-1.9 + 1.5	-2.4 + 2.3	-2.4 + 3.1

According to the findings, there was collectively a decrease in fat-free mass (FFM), blood pressure, glucose, insulin, A1c, triglycerides, total cholesterol, and LDL cholesterol.  In Table 3, the exercise groups had greater reductions in fat mass (p <0.01) and WC (p <0.01) than the diet only participants.  When compared with the other groups, the high protein and resistance exercise group showed the greatest weight loss, 3.3 kg greater than other groups, and 21% greater reduction in waist circumference.

The reduction in insulin and A1c was not significantly different in the groups. However, in the HP+RT group there was a two-fold lower fasting insulin difference compared to the other groups.  The reduced insulin reduction in the high protein and resistance-training group may be linked to the high fat mass reduction.  Insulin correlated with both weight changes (r= 0.35) and fat mass (r= 0.36) and insulin resistance is directly driven by fat mass accumulation.  Improvements were not seen in A1c with resistance training, as previously noted in another study (Sigal, et al., 2007).  A1c reductions have been associated with a 21% reduction in diabetes related mortality.  

Overall it can be suggested that higher ratios of protein (1.12-1.5 g/kg) to carbohydrates will help to sustain energy, reduce hunger, and increase satiety (Ballor et al., 1988; Layman, et al., 2003; Wycherley et al., 2010).  These studies also suggest that an increase in the protein to carbohydrate ratio promotes muscle synthesis and maintain lean body mass in a catabolic state.  It is imperative to incorporate negative caloric balance of exercise and not calorically restrict dietary intake (Robb-Nicholson, 2010).

VI. CONCLUSION
The prevalence of obesity and health related complications, like lipotoxicity, insulin resistance, and type 2 diabetes, is rising across the United States and a weight loss treatment is needed  (Volpe et al., 2008).  Obesity is an imbalance of energy intake and expenditure, and the over accumulation of body fat compromises the vitality of tissues and organs throughout the body.  These complications manifest into lipotoxicity and are related to impaired insulin sensitivity at peripheral tissues and type 2 diabetes.  Today, the most common weight loss treatment for obesity is restrictive dieting, like the HCG protocol (Ross, et al., 2000).  However, according to research, these diets are linked to muscle loss, detrimental changes in metabolic pathways, and weight regain (Biolo, et al., 2007).  One of the cofounding factors that contribute to obesity is energy expenditure (exercise).  Research has shown that exercise alone enhances carbohydrate and lipid metabolism, improves lean body mass, but shows only modest weight loss advances (Holten et al., 2004).  Therefore, combining diet and exercise interventions has shown to significantly lower fat mass, improve metabolic health, and maintain fat free mass.  In addition, various studies have shown that supplementing slightly higher ratios of protein to carbohydrates in a diet, may promote anabolic muscle mass growth in a catabolic state of moderate caloric reductions (Ballor et al., 1988; Wycherley et al., 2010; Layman, et al., 2003).

According to various studies, combining physical activity and moderate caloric reductions, with the proper ratio of protein and carbohydrates: promotes fat loss, maintains and elicits gains in lean body mass, and enhances metabolic health (Layman, et al., 2003).  This type of treatment for obesity has been shown most effective because it creates energy balance in the body and regulates the metabolism.  In addition, it promotes fat loss and maintains lean body mass content.  In short, the combination of diet and exercise has been shown the most effective weight loss treatment for obesity than diet or exercise alone.  

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